# Patent

## Title
Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase 4 and/or other PTPases with an Asp residue at position 48

## Abstract

The present invention provides a method of inhibiting a member of a family of Protein Tyrosine Phosphatases (PTPases, PTPs) such as PTP1B, TC-PTP, CD45, SHP-1, SHP-2, PTPα, PTPε, PTPμ, PTPδ, PTPσ, PTPζ, PTPβ, PTPD1, PTPD2, PTPH1, PTP-MEG1, PTP-LAR, and HePTP by exposing said Ptpase member by administration to a host or otherwise to at least one compound with certain structural, physical and spatial characteristics that allow for the interaction of said compound with specific residues of the active site of PTP1B and/or TC-PTP. These compounds are indicated in the management or treatment of a broad range of diseases such as autoimmune diseases, acute and chronic inflammation, osteoporosis, various forms of cancer and malignant diseases, and type I diabetes and type II diabetes, as well as in the isolation of PTPases and in elucidation or further elucidation of their biological function.

## Background
This patent application claims the priority of (1) U.S. provisional patent application No. 60/156,641, filed Sep. 29, 1999, (2) Danish Patent Application No. PA 1999 01279, filed Sep. 10, 1999, and (3) U.S. Ser. No. 09/268,490, filed Mar. 11, 1999, now U.S. Pat. No. 6,262,044, which claims the benefit of U.S. Provisional Patent Application Nos. 60/082,915, 60/093,525, and 60/108,747, filed Apr. 24, 1998, Jul. 21, 1998, and Nov. 17, 1998, respectively, and Danish Patent Application Nos. 0344/98, PA 1998 00480, PA 1998 00938, PA 1998 01385, and PA 1998 10612, filed Mar. 12, 1998, Apr. 3, 1998, Jul. 15, 1998, Oct. 28, 1998, and Dec. 7, 1998, respectively, each of which is incorporated herein by reference.


FIELD OF THE INVENTION
This invention relates to a method of inhibiting Protein Tyrosine Phosphatase 1B (PTP1B) and/or T-cell Protein Tyrosine Phosphatase (TC-PTP) and/or Protein Tyrosine Phosphatases (PTPases) having an aspartic acid (Asp) in position 48 (PTP1B numbering, Chernoff et al., Proc. Natl. Acad. Sci. USA 87: 2735–2789 (1989)) by exposing such an enzyme to inhibitor compounds, i.e., to compounds possessing certain structural, physico-chemical and spatial characteristics that allow them to interact with specific amino acid residues of the active site (and the vicinity of the active site) of PTP1B and/or TC-PTP and more generally Protein Tyrosine Phosphatases (PTPases) having an aspartic acid (Asp) in position 48. The resulting inhibition of the PTPase enzymatic activity makes these compounds useful for elucidating the function of PTP's e.g., by inhibiting a PTP and observing up- or down-regulation of other proteins. Additionally, such inhibitors serve as early development candidates, development candidates, or prototype drugs for treatment of or paliation of diseases and dysfunctions such as diabetes type I and II and obesity, cancer, immune disorders (including-allergy and abnormal autoimmunity), and conditions involving disturbances in platelet aggregation as well as infectious diseases. This invention also relates to (I) the design and selection of inhibitors which bind to the active site of PTP1B and/or TC-PTP and/or PTPases having an aspartic acid (Asp) in position 48 (II) the synthesis of said inhibitors, methods for their preparation and (III) to compositions comprising the inhibitor compounds.
BACKGROUND OF THE INVENTION
Protein phosphorylation is now well recognized as an important mechanism utilized by cells to transduce and regulate signals during different stages of cellular function (Hunter, Phil. Trans. R. Soc. Lond. B 353: 583–605 (1998); Chan et al., Annu. Rev. Immunol. 12: 555–592 (1994); Zhang, Curr. Top. Cell. Reg. 35: 21–68 (1997); Matozaki and Kasuga, Cell. Signal. 8: 113–19 (1996); Fischer et al, Science 253:401–6 (1991); Flint et al., EMBO J. 12:1937–46 (1993)). The level of tyrosine phosphorylation is balanced by the opposing action of protein tyrosine kinases and protein tyrosine phosphatases. There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
The PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases. In addition, dual-specificity phosphatases and low molecular weight phosphatases are able to dephosphorylate phospho tyrosyl proteins. See, e.g., WO 97/39746; WO 97/40017; WO 99/15529; WO 97/08934; WO 98/27065; WO 99/46236; WO 99/46244; WO 99/46267; WO 99/46268 and WO 99/46237.
Intracellular PTPases: Most known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220–240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intracellular PTPases subcellularly (Mauro, L. J. and Dixon, J. E. TIBS 19: 151–155 (1994)). The first intracellular PTPase to be purified and characterized was PTP1B, which was isolated from human placenta (Tonks et al., J. Biol. Chem. 263: 6722–6730 (1988)). Shortly after, PTP1B was expressed recombinantly (Charbonneau et al., Proc. Natl. Acad. Sci. USA 86: 5252–5256 (1989); Chernoff et al., Proc. Natl. Acad. Sci. USA 87: 2735–2789 (1989)). Other examples of intracellular PTPases include (1) T-cell PTPase/TC-PTP (Cool et al. Proc. Natl. Acad. Sci. USA 86: 5257–5261 (1989)), (2) rat brain PTPase (Guan et al., Proc. Natl. Acad. Sci. USA 87:1501–1502 (1990)), (3) neuronal phosphatase STEP (Lombroso et al., Proc. Natl. Acad. Sci. USA 88: 7242–7246 (1991)), (4) ezrin-domain containing PTPases: PTPMEG1 (Guet al., Proc. Natl. Acad. Sci. USA 88: 5867–57871 (1991)). PTPH1 (Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949–5953 (1991)), PTPD1 and PTPD2 (Møller et al., Proc. Natl. Acad. Sci. USA 91: 7477–7481 (1994)); FAP-1/BAS (Sato et al., Science 268: 411–415 (1995); Banville et al., J. Biol. Chem. 269, 22320–22327 (1994); Maekawa et al., FEBS Letters 337: 200–206 (1994)), and SH2 domain containing PTPases: PTP1C/SH-PTP1/SHP-1 (Plutzky et al., Proc. Natl. Acad. Sci. USA 89: 1123–1127 (1992); Shen et al., Nature Lond. 352: 736–739 (1991)) and PTP1D/Syp/SH-PTP2/SHP-2 (Vogel et al., Science 259: 1611–1614 (1993); Feng et al., Science 259: 1607–1611 (1993); Bastein et al., Biochem. Biophys. Res. Comm. 196: 124–133 (1993)).
Receptor-type PTPases consist of a) a putative ligand-binding extracellular domain, b) a transmembrane segment, and c) an intracellular catalytic region. The structures and sizes of the putative ligand-binding extracellular domains of receptor-type PTPases are quite divergent. In contrast, the intracellular catalytic regions of receptor-type PTPases are very homologous to each other and to the intracellular PTPases. Most receptor-type PTPases have two tandemly duplicated catalytic PTPase domains.
The first receptor-type PTPases to be identified were (1) CD45/LCA (Ralph, S. J., EMBO J. 6: 1251–1257 (1987)) and (2) LAR (Streuli et al., J. Exp. Med. 168: 1523–1530 (1988)) that were recognized to belong to this class of enzymes based on homology to PTP1B (Charbonneau et al., Proc. Natl. Aced. Sci. USA 86: 5252–256 (1989)). CD45 is a family of high molecular weight glycoproteins and is one of the most abundant leukocyte cell surface glycoproteins and appears to be exclusively expressed upon cells of the hematopoietic system (Trowbridge and Thomas, Ann. Rev. Immunol. 12: 85–116 (1994)).
The identification of CD45 and LAR as members of the PTPase family was quickly followed by identification and cloning of several different members of the receptor-type PTPase group. Thus, 5 different PTPases, (3) PTPα, (4) PTPβ, (5) PTPδ, (6) PTPε, and (7) PTPζ, were identified in one early study (Krueger et al., EMBO J. 9: 3241–3252 (1990)). Other examples of receptor-type PTPases include (8) PTPγ(Barnea et al., Mol. Cell. Biol. 13: 1497–1506 (1995)) which, like PTPζ (Krueger and Saito, Proc. Natl. Acad. Sci. USA 89: 7417–7421 (1992)) contains a carbonic anhydrase-like domain in the extracellular region, (9) PTPμ (Gebbink et al., FEBS Letters 290: 123–130 (1991)), (10) PTPκ (Jiang et al., Mol. Cell. Biol. 13: 2942–2951 (1993)). Based on structural differences the receptor-type PTPases may be classified into subtypes (Fischer et al., Science 253: 401–406 (19991)): (I) CD45; (II) LAR, PTPd, (11) PTPσ; (III) PTPβ, (12) SAP-1 (Matozaki et al., J. Biol. Chem. 269: 2075–2081 (1994)), (13) PTP-U2/GLEPP1 (Seimiya et al., Oncogene 10: 1731–1738 (1995); Thomas et al., J. Biol. Chem. 269: 19953–19962 (1994)), and (14) DEP-1; (IV) PTPα,_PTPε. All receptor-type PTPases except Type III contain two PTPase domains. Novel PTPases are frequently identified, and it is anticipated that between 100 and more than 500 different species will be found in the human genome.
PTPases are the biological counterparts to protein tyrosine kinases (PTKs). Therefore, one important function of PTPases is to control, and especially down-regulate, the activity of PTKs. However, a more complex picture of the function of PTPases has emerged. Thus, several studies indicate that some PTPases act as positive mediators of cellular signaling. As an example, the SH2 domain-containing SHP-2 acts as a positive mediator in insulin-stimulated Ras activation (Noguchi et al., Mol. Cell. Biol. 14: 6674–6682 (1994)) and of growth factor-induced mitogenic signal transduction (Xiao et al., J. Biol. Chem. 269: 21244–21248 (1994)), whereas the homologous SHP-1 acts as a negative regulator of growth factor-stimulated proliferation (Bignon and Siminovitch, Clin. Immunol. Immunopathol. 73: 168–179 (1994)). Another example of PTPases as positive regulators has been provided by studies designed to define the activation of the Src-family of tyrosine kinases. In particular, several lines of evidence indicate that CD45 is positively regulating the activation of hematopoietic cells, and that the mechanism of such positive regulation may involve dephosphorylation of the C-terminal tyrosine of Fyn and Lck (Chan et al., Annu. Rev. Immunol. 12: 555–592 (1994)).
The association of many PTPases with cell proliferation, tranformation and differentiation has now been established. PTP1B, a phosphatase whose structure was the first PTPase to be elucidated (Barford et al., Science 263:1397–1404 (1994)) has been shown to be involved in insulin-induced oocyte maturation (Flint et al., The EMBO J. 12:1937–46 (1993)) and the overexpression of this enzyme has been implicated in p185c-erb B2-associated breast and ovarian cancers (Weiner, et al., J. Natl. cancer Inst. 86:372–8 (1994); Weiner et al., Am. J. Obstet. Gynecol. 170:1177–883 (1994)). The association with cancer is on the basis of evidence that overexpression of PTP1B is statistically correlated with increased levels of p185 c-erb B2 in ovarian and breast cancer. The role of PTP1B in the etiology and progression of the disease has not yet been elucidated. Inhibitors of PTP1B therefore would help clarify the role of PTP1B in cancer and in some cases provide therapeutic treatment for certain forms of cancer.
PTPases: the Insulin Receptor Signaling Pathway/Diabetes
Insulin is an important regulator of different metabolic processes and plays a key role in the control of blood glucose. Defects related to its synthesis or signaling lead to diabetes mellitus. Binding of insulin to the insulin receptor (IR) causes rapid (auto)phosphorylation of several tyrosine residues in the intracellular part of the β-subunit. Three closely positioned tyrosine residues (the tyrosine-1150 domain) must all be phosphorylated to obtain full activity of the insulin receptor tyrosine kinase (IRTK) which transmits the signal further downstream by tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) (Wilden et al., J. Biol. Chem. 267: 16660–16668 (1992); Myers and White, Diabetes 42: 643–650 (1993); Lee and Pilch, Am. J. Physiol. 266: C319–C334 (1994); White et al., J. Biol. Chem. 263: 2969–2980 (1988)). The structural basis for the function of the tyrosine-triplet has been provided by X-ray crystallographic studies of IRTK that showed the tyrosine-1150 domain to be autoinhibitory in its unphosphorylated state (Hubbard et al, Nature 372: 746–754 (1994)) and of the activated IRTK (Hubbard, EMBO J. 16: 5572–5581 (1997)).
Several studies clearly indicate that the activity of the auto-phosphorylated IRTK can be reversed by dephosphorylation in vitro (reviewed in Goldstein, Receptor 3: 1–15 (1993); Mooney and Anderson, J. Biol. Chem. 264: 6850–6857 (1989)), with the tri-phosphorylated tyrosine-1150 domain being the most sensitive target for protein-tyrosine phosphatases (PTPases) as compared to the di- and mono-phosphorylated forms (King et al., Biochem. J. 275: 413–418 (1991)). This tyrosine-triplet functions as a control switch of IRTK activity and IRTK appears to be tightly regulated by PTP-mediated dephosphorylation in vivo (Khan et al., J. Biol. Chem. 264: 12931–12940 (1989); Faure et al., J. Biol. Chem. 267: 11215–11221 (1992); Rothenberg et al., J. Biol. Chem. 266: 8302–8311 (1991)). The intimate coupling of PTPases to the insulin signaling pathway is further evidenced by the finding that insulin differentially regulates PTPase activity in rat hepatoma cells (Meyerovitch et al., Biochemistry 31: 10338–10344 (1992)) and in livers from alloxan diabetic rats (Boylan et al., J. Clin. Invest 90:174–179 (1992)).
Until recently, relatively little was known about the identity of the PTPases involved in IRTK regulation. However, the existence of PTPases with activity towards the insulin receptor can be demonstrated as indicated above. Further, when the strong PTPase-inhibitor pervanadate is added to whole cells an almost full insulin response can be obtained in adipocytes (Fantus et al., Biochemistry 28: 8864–8871 (1989); Eriksson et al., Diabetologia 39: 235–242 (1995)) and skeletal muscle (Leighton et al., Biochem: J. 276: 289–292 (1991)). In addition, other studies show that a new class of peroxovanadium compounds act as potent hypoglycemic compounds in vivo (Posner et al., supra). Two of these compounds were demonstrated to be more potent inhibitors of dephosphorylation of the insulin receptor than of the EGF-receptor, thus indicating that even such relatively unselective inhibitors may show some specificity in regulating different signal transduction pathways.
It was recently found that mice lacking the protein tyrosine phosphatase-1B gene (PTP1B) (Elchebly et al., Science 283: 1544–1548 (1999)) yielded healthy mice that showed increased insulin sensitivity and were resistant to diet-induced obesity. These results were confirmed by Kaman at al Mol. Cell Biol. 20:5479–5489 (2000). The enhanced insulin sensitivity of the PTP−/− mice was also evident in glucose and insulin tolerance tests.
The PTP-1B knock-out mouse showed many characteristics which would be highly desirable results for an anti-diabetes treatment. Most importantly, the knock-out mice grew normally and were fertile and have exhibited no increased incidence of cancer. Blood glucose and insulin levels were lowered, and insulin sensitivity increased. Moreover, the insulin-stimulated tyrosine phosphorylation levels of IR and IRS-1 were found to be increased/prolonged in muscle and liver—but not in fat tissue. Thus, the main target tissues for this type of approach would appear to be insulin action in liver and muscle.
Several other “diabetic” parameters were also improved, including plasma triglycerides which were decreased in the knock-out mice. The knock-animals also exhibited a resistance to weight gain when placed on a high-fat diet. This is in contrast to the action of the PPARγ agonist class of insulin sensitizers, which rather induce weight gain (Murphy & Nolan, Exp. Opin. Invest. Drugs 9:1347–1361, 2000), and would suggest that inhibition of PTP-1B could be a particularly attractive option for treatment of obese Type II diabetics.
This is also supported by the fact that the heterozygous mice from this study showed many of these desirable features. The reduction in weight gain of the knock-out animals on the high fat diet was found to be due to a decreased fat cell mass, although differences were observed with respect to fat cell number. Leptin levels were also lower in the knock-out mice, presumably as a reflection of the decreased fat mass. Significantly, the Klaman et al group also found that the knock-out animals had an increased energy expenditure of around 20% and an increased respiratory quotient compared to the wild-type; again, heterozygote animals displayed an intermediate level of energy expenditure. Therefore, inhibition of this enzyme may be an effective anti-diabetic and perhaps also anti-obesity therapy.
It should also be rioted that in the PTP-1B knock-out mice the basal tyrosine phosphorylation level of the insulin receptor tyrosine kinase does not appear to be increased, which is in contrast to the situation after insulin treatment where there is an increased or prolonged phosphorylation. This might indicate that other PTPs are controlling the basic phosphorylation state of the insulin receptor in the knock-out mice—and is expected to do so in man.
Also other PTPases have been implicated as regulators of the insulin signaling pathway. Thus, it was found that the ubiquitously expressed SH2 domain containing PTPase, PTP1 D/SHP-2 (Vogel et al., 1993, supra), associates with and dephosphorylates IRS-1, but apparently not the IR it self (Kuhné et al., J. Biol. Chem. 268: 11479–11481 (1993); (Kuhné et al., J. Biol. Chem. 269: 15833–15837 (1994)).
Other studies suggest that receptor-type or membrane-associated PTPases are involved in IRTK regulation (Faure et al., J. Biol. Chem. 267: 11215–11221 (1992), (Haring et al., Biochemistry 23: 3298–3306 (1984); Sale, Adv. Prot. Phosphatases 6: 159–186 (1991)).
While previous reports indicate a role of PTPα in signal transduction through src activation (Zheng et al., Nature 359: 336–339 (1992); den Hertog et al., EMBO J. 12: 3789–3798 (1993)) and interaction with GRB-2 (den Hertog et al., EMBO J. 13: 3020–3032 (1994); Su et al., J. Biol. Chem. 269: 18731–18734 (19.94)), Møller, Lammers and coworkers provided results that suggest a function for this phosphatase and its close relative PTPε as negative regulators of the insulin receptor signal (Møller et al., 1995 supra; Lammers, et al., FEBS Lett. 404:37–40 (1997). These studies also indicated that receptor-like PTPases may play a significant role in regulating the IRTK, including through direct influence on the insulin receptor itself.
Other studies have shown that PTP1B and TC-PTP are likely to be involved in the regulation of several other cellular processes in addition to the described regulatory roles in insulin signaling. Therefore, PTP1B and/or TC-PTP as well as other PTPases showing key structural features with PTP1B and TC-PTP are likely to be important therapeutic targets in a variety of human and animal diseases. The compounds of the present invention are useful for modulating or inhibiting PTP1B and/or TC-PTP and/or other PTPases showing key structural features with said PTPases and thus elucidating their function and for treating disease states in which said modulation or inhibition is indicated.
Further, PTPases influence the following hormones or diseases or disease states: somatostatin, the immune system/autoimmunity, cell—cell interactions/cancer, platelet aggregation, osteoporosis, and microorganisms, as disclosed in PCT Publication WO 99/15529.
PTPases: the Immune System/Autoimmunity
Several studies suggest that the receptor-type PTPase CD45 plays a critical role not only for initiation of T cell activation, but also for maintaining the T cell receptor-mediated signaling cascade. These studies are reviewed in: (Weiss A., Ann. Rev. Genet. 25: 487–510 (1991); Chan et al., Annu. Rev. Immunol. 12: 555–592 (1994); Trowbridge and Thomas, Annu. Rev. Immunol. 12: 85–116 (1994)).
CD45 is one of the most abundant of the cell surface glycoproteins and is expressed exclusively on hemopoetic cells. In T cells, it has been shown that CD45 is one of the critical components of the signal transduction machinery of lymphocytes. In particular, there is evidence that CD45 phosphatase plays a pivotal role in antigen-stimulated proliferation of T lymphocytes after an antigen has bound to the T cell receptor (Trowbridge, Ann. Rev. Immunol, 12: 85–116 (1994)). Several studies indicate that the PTPase activity of CD45 plays a role in the activation of Lck, a lymphocyte-specific member of the Src family protein-tyrosine kinase (Mustelin et al., Proc. Natl. Acad. Sci. USA 86: 6302–6306 (1989); Ostergaard et al., Proc. Natl. Acad. Sci. USA 86: 8959–8963 (1989)). Studies using transgenic mice with a mutation for the CD45-exon6 exhibited a lack of mature T cells. These mice did not respond to an antigenic challenge with the typical T cell mediated response (Kishihara et al., Cell 74:143–56 (1993)). Inhibitors of CD45 phosphatase would therefore be very effective therapeutic agents in conditions that are associated with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. Another important function of CD45 phosphatase inhibitors is in effecting immunosuppression, where such a result is indicated, e.g., in transplantation and other conditions in need of immunosuppressive treatment.
CD45 has also been shown to be essential for the antibody mediated degranulation of mast cells (Berger et al., J. Exp. Med. 180:471–6 (1994)). These studies were also done with mice that were CD45-deficient. In this case, an IgE-mediated degranulation was demonstrated in wild type but not CD45-deficient T cells from mice. These data suggest that CD45 inhibitors could also play a role in the symptomatic or therapeutic treatment of allergic disorders, such as asthma, allergic rhinitis, food allergies, eczema, urticaria and anaphylaxis. Another PTPase, an inducible lymphoid-specific protein tyrosine phosphatase (HePTP) has also been implicated in the immune response. This phosphatase is expressed in both resting T and B lymphocytes, but not non-hemopoetic cells. Upon stimulation of these cells, mRNA levels from the HePTP gene increase 10–15 fold (Zanke et al., Eur. J. Immunol. 22: 235–239 (1992)).
Likewise, the hematopoietic cell specific SHP-1 acts as a negative regulator and thus appears to play an essential role in immune cell development in accordance with the above-mentioned important function of CD45, HePTP and SHP-1, selective PTPase inhibitors are early development candidates or prototype drugs both as immunosuppressors and as immunostimulants. Recent studies illustrate the potential of PTPase inhibitors as immunmodulators by demonstrating the capacity of the vanadium-based relatively nonselective PTPase inhibitor, BMLOV, to induce apparent B cell selective apoptosis compared to T cells (Schieven et al., J. Biol. Chem. 270: 20824–20831 (1995)).
PTPases: Cell—Cell Interactions/Cancer
Focal adhesion plaques, an in vitro phenomenon in which specific contact points are formed when fibroblasts grow on appropriate substrates, mimic, in certain respects, cells and their natural surroundings. Several focal adhesion proteins are phosphorylated on tyrosine residues when fibroblasts adhere to and spread on extracellular matrix (Gumbiner, Neuron 11: 551–564 (1993)). However, aberrant tyrosine phosphorylation of these proteins can lead to cellular transformation. The intimate association between PTPases and focal adhesions is supported by the finding of several intracellular PTPases with ezrin-like N-terminal domains, e.g. PTPMEG1 (Gu et al., Proc. Natl. Acad. Sci. USA 88: 5867–5871 (1991), PTPH1 (Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949–5953 (1991)) and PTPD1 (Møller et al., Proc. Natl. Acad. Sci. USA 91: 7477–7481 (1994)). The ezrin-like domains show similarity to several proteins that are believed to act as links between the cell membrane and the cytoskeleton. PTPD1 was found to be phosphorylated by and associated with c-src in vitro and is hypothesized to be involved in the regulation of phosphorylation of focal adhesions (Møller et al., supra).
PTPases may oppose the action of tyrosine kinases, including those responsible for phosphorylation of focal adhesion proteins, and may therefore function as natural inhibitors of transformation. TC-PTP, and especially the truncated form of this enzyme (Cool et al., Proc. Natl. Acad. Sci. USA 87: 7280–7284 (1990)), can inhibit the transforming activity of v-erb and v-fms (Lammers et al., J. Biol. Chem. 268: 22456–22462 (1993), Zander et al., Oncogene 8: 1175–1182 (1993)). Moreover, it was found that transformation by the oncogenic form of the HER2/neu gene was suppressed in NIH 3T3 fribroblasts overexpressing PTP1B (Brown-Shimer et al., Cancer Res. 52: 478482 (1992)).
The expression level of PTP1B was found to be increased in a mammary cell line transformed with neu (Zhay et al., Cancer Res. 53: 2272–2278 (1993)). The intimate relationship between tyrosine kinases and PTPases in the development of cancer is further evidenced by the recent finding that PTPe is highly expressed in murine mammary tumors in transgenic mice over-expressing c-neu and v-Ha-ras, but not c-myc or int-2 (Elson and Leder, J. Biol. Chem. 270: 26116–26122 (1995)). Further, the human gene encoding PTPγ was mapped to 3p21, a chromosomal region which is frequently deleted in renal and lung carcinomas (LaForgia et al., Proc. Natl. Acad. Sci. USA 88: 5036–5040 (1991)).
PTPases appear to be involved in controlling the growth of fibroblasts. In a recent study it was found that Swiss 3T3 cells harvested at high density contain a membrane-associated PTPase whose activity on an average is 8-fold higher than that of cells harvested at low or medium density (Pallen and Tong, Proc. Natl. Acad. Sci. USA 88: 6996–7000 (1991)).
Two closely related receptor-type PTPases, PTPκ and PTPμ, can mediate homophilic cell—cell interaction when expressed in non-adherent insect cells, suggesting that a normal physiological function for these PTPases in cell-to-cell signalling (Gebbink et al., J. Biol. Chem. 268: 16101–16104 (1993), Brady-Kalnay et al., J. Cell Biol. 122: 961–972 (1993); Sap et al., Mol. Cell. Biol. 14: 1–9 (1994)). Interestingly, PTPκ and PTPμ do not bind to each other (PTPκ does self-associate), despite their structural similarity (Zondag et al., J. Biol. Chem. 270: 14247–14250 (1995)).
From the studies described above it is apparent that PTPases play an important role in regulating normal cell growth. Additionally, as pointed out above, PTPases may also function as positive mediators of intracellular signaling and thereby induce or enhance mitogenic responses. Increased activity of certain PTPases might therefore result in cellular transformation and tumor formation. See, Zheng, supra; Uchida et al., J. Biol. Chem. 269: 12220–12228 (1994 Hunter, Cell 80: 225–236 (1995). Inhibitors of specific PTPases are therefore likely to be of significant therapeutic value in the treatment of certain forms of cancer.
PTPases: Platelet Aggregation
PTPases are centrally involved in platelet aggregation. Thus, agonist-induced platelet activation results in calpain-catalyzed cleavage of PTP1B with a concomitant 2-fold stimulation of PTPase activity (Frangioni et al., EMBO J. 12: 4843–4856 (1993)). The cleavage of PTP1B leads to subcellular relocation of the enzyme and correlates with the transition from reversible to irreversible platelet aggregation in platelet-rich plasma. In addition, the SH2 domain containing PTPase, SHP-1, was found to translocate to the cytoskeleton in platelets after thrombin stimulation in an aggregation-dependent manner (Li et al., FEBS Lett. 343: 89–93 (1994)).
Although some details in the above two studies have been questioned, there is overall agreement that PTP1B and SHP-1 play significant functional roles in platelet aggregation (Ezumi et al., J. Biol. Chem. 270: 11927–11934 (1995)). In accordance with these observations, treatment of platelets with the PTPase inhibitor pervanadate leads to significant increase in tyrosine phosphorylation, secretion and aggregation (Pumiglia et al., Biochem. J. 286: 441–449 (1992)).
PTPases: Osteoporosis
The rate of bone formation is determined by the number and the activity of osteoblasts. In turn, these are determined by the rate of proliferation and differentiation of osteoblast progenitor cells, respectively. Histomorphometric studies indicate that the osteoblast number is the primary determinant of the rate of bone formation in humans (Gruber et al., Mineral Electrolyte Metab. 12: 246–254 (1987), reviewed in Lau et al., Biochem. J. 257: 23–36 (1989)). Acid phosphatases/PTPases are implicated in negative regulation of osteoblast proliferation. Thus, fluoride, which has phosphatase inhibitory activity, has been found to increase spinal bone density in osteoporotics by increasing osteoblast proliferation (Lau et al.; supra). Consistent with this observation, an osteoblastic acid phosphatase with PTPase activity was found to be highly sensitive to mitogenic concentrations of fluoride (Lau et al., J. Biol. Chem. 260: 4653–4660 (1985), Lau et al., J. Biol. Chem. 262: 1389–1397 (1987), Lau et al., Adv. Protein Phosphatases 4: 165–198 (1987)). The mitogenic action of fluoride and other phosphatase inhibitors (molybdate and vanadate) may thus be explained by their inhibition of acid phosphatases/PTPases that negatively regulate the cell proliferation of osteoblasts. The complex nature of the involvement of PTPases in bone formation is further suggested by the recent identification of a novel parathyroid regulated, receptor-like PTPase, OST-PTP, expressed in bone and testis (Mauro et al., J. Biol. Chem. 269: 30659–30667 (1994)). OST-PTP is up-regulated following differentiation and matrix formation of primary osteoblasts and subsequently down-regulated in the osteoblasts which are actively mineralizing bone in culture. In addition, it was recently observed that vanadate, vanadyl and pervanadate all increased the growth of the osteoblast-like cell line UMR106. Vanadyl and pervanadate were stronger stimulators of cell growth than vanadate. Only vanadate was able to regulate the cell differentiation as measured by cell alkaline phosphatase activity (Cortizo et al., Mol. Cell. Biochem. 145: 97–102 (1995)). More important, several studies have shown that biphosphonates, such as alendronate and tiludronate, inhibit PTPase activity in osteoclasts and that the inhibition of PTPase activity correlated with the inhibition of in vitro osteoclast formation and bone resorption. (Scmidt, et al., Proc. Natl. Acad. Sci. U.S.A. 93: 3068–3073, 1996; Murakami et al., Bone 20:399–404, 1997; Opas et al., Biochem. Pharmacol. 54: 721–727, 1997; Skorey et al., J. Biol. Chem. 272: 22472–22480, 1997. Thus other PTPase inhibitors are potentially effective in countering osteoclast activity, and thus treating osteoporosis.
PTPases: Microorganisms
Dixon and coworkers have called attention to the fact that PTPases may be a key element in the pathogenic properties of Yersinia (reviewed in Clemens et al. Molecular Microbiology 5: 2617–2620 (1991)). This finding was rather surprising since tyrosine phosphate is thought to be absent in bacteria. The genus Yersinia comprises 3 species: Y. pestis (responsible for the bubonic plague), Y. pseudoturberculosis and Y. enterocolitica (causing enteritis and mesenteric lymphadenitis). A dual-specificity phosphatase, VH1, has been identified in Vaccinia virus (Guan et al., Nature 350: 359–263 (1991)). These observations indicate that PTPases may play critical roles in microbial and parasitic infections, and they further point to PTPase inhibitors as a novel, putative treatment principle of infectious diseases. Availibility of PTPase inhibitors would help shed light in all the foregoing specualations about PTPase function because they would enable assaying techniques which would answer some of these questions as will be illustrated below.
SUMMARY OF BACKGROUND
It has been found that PTPases play a major role in the above modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fisher et al, Science 253:401–6 (1991); Tonks and Neel, Cell 87: 365–368 (1966)” Neel and Tonks, Current Opinion in Cell Biology 9: 193–204 (1997); Hunter, Phil. Trans. R. Soc. Lond. B 353: 583–605 (1998); Hunter, Cell 100: 113–120 (2000); Zhang, Critical Reviews in Biochemistry and Molecular Biology 33:1–52 (1988)). Reports from many laboratories have shown that PTPases can act both as positive and negative regulators of signal transduction processes. PTPases have been implicated in a variety of human diseases, including diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis, proliferative disorders including various forms of cancer, growth disorders, and defective platelet aggregation (WO97/39748, WO97/40017, WO99/1529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237). Accordingly there is increasing evidence which suggests that inhibition of these PTPases would help treat or manage these diseases (Hunter, vide supra; Neel and Tonks, vide supra: Frangione et al., EMBO J. 12:4843–4856 (1993); Zhang, Curr. Top. Cell. Reg. 35, 21–68 (1997): Zhang, vide supra; Evans and Jalian, Exp. Opinion. Invest Drugs 8: 139–160 (1999); Burke and Zhang, Bioploymers (Peptide Science) 47: 225–241 (1998): Elchebly et al.; Science 283: 1544–1548 (1999); Wrobel et al., J. Med. Chem. 42: 3199–3202 (1999)). In addition, certain infectious diseases may also be treated or managed by administration PTPase inhibitors (Clemens et al., Molecular Microbiology 5: 2617–2620 (1991)).
Both selective PTPase inhibitors and inhibitors that bind to several PTPases (non-selective inhibitors) can be used therapeutically to partially or completely restore PTPase-mediated perturbed signal transduction processes and thus for management, treatment, palliation or prevention of the above diseases.



DESCRIPTION OF DRAWINGS
FIG. 1. Active site of Protein Tyrosine Phosphatase 1B complexed with with 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid.
FIG. 2. Active site of Protein Tyrosine Phosphatase 1B complexed with 7-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (Example 26).
FIG. 3. Active site of Protein Tyrosine Phosphatase 1B complexed with 5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (Example 4).
FIG. 4. Active site of Protein Tyrosine Phosphatase 1B complexed with 2-(oxalyl-amino)-7-(1,1,3-trioxo-1H-benzo[d]isothiazol-3-yloxomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (Example 54). Selected water molecules are shown.



DESCRIPTION OF THE INVENTION
The present invention provides a method for inhibiting protein tyrosine phosphatase 1B (PTP1B) and/or T-cell protein tyrosine phosphatase (T-cell PTP/TC-PTP) and/or protein tyrosine phosphatases (PTPases) having an aspartic acid (Asp) in position 48 by exposing said PTPase to a compound having physico-chemical and spatial structural characteristics that interfere with the active site and/or vicinity of the active site of said PTPase thereby inhibiting its enzymatic activity. Specifically, the present inhibitors of PTP1B and/or TC-PTP and/or PTPases having an aspartic acid (Asp) in position 48 interact with two or more residues of the following: arginine 221, glycine 220, lysine 120, tyrosine 46, and phenylalanine/histidine 182 and one or more of the following (residue numbering corresponding to PTP1B will be used through out (Chernoff et al., Proc. Natl. Acad. Sci. USA 87: 2735–2789 (1989)):
1. Isoleucine 219 backbone amide nitrogen;
2. Glycine 218 backbone amide nitrogen;
3. Alanine 217 backbone amide nitrogen;
4. Serine 216 backbone amide nitrogen;
5. Cysteine 215 backbone amide nitrogen;
6. The side chain carboxylic acid group of aspartic acid 181;
7. The side chain carboxylic acid group of aspartic acid 48;
8. The side chain guanidinium group of arginine 47;
9. Arginine 47 backbone amide nitrogen;
10. Aspartic acid 48 backbone amide nitrogen;
11. The side chain hydroxy group of tyrosine 46;
12. The side chain amino group of lysine 41;
13. The methylene side chain atoms of lysine 41;
14. The backbone amide carbonyl of asparagine 44;
15. The methylene side chain atoms of arginine 45;
16. The backbone amide carbonyl of arginine 45;
17. The methylene side chain atoms of arginine 47;
18. The methylene side chain atom of aspartic acid 48;
19. The backbone amide carbonyl of aspartic acid 48;
20. The methylene side chain atoms of leucine 88;
21. The side chain hydroxy group of serine 118;
22. The backbone amide carbonyl of leucine 119;
23. The side chain amide nitrogen of glutamine 262;
24. The side chain atoms of methionine 258;
25. The aromatic group of phenylalanine 52;
26. The backbone amide nitrogen of glycine 259;
27. The alpha-methylene atom of glycine 259;
28. The guanidinium group of arginine 254;
29. The methylene side chain atoms of arginine 254;
30. The methylene side chain atoms of arginine 24;
31. The guanidinium group of arginine 24; or
32. Any conserved water molecule in the vicinity of the active site.
Preferably, the present inhibitors of PTP1B and/or TC-PTP and/or PTPases having an aspartic acid (Asp) in position 48 interact with any three or more of the above identified regions of the active site and its vicinity.
In one preference, the inhibitors of PTP1B and/or TC-PTP and/or PTPases having an aspartic acid (Asp) in position 48 interact with arginine 221, glycine 220, lysine 120, tyrosine 46, phenylalanine/histidine 182, aspartic acid 48 and one or more of the following
1. Isoleucine 219 backbone amide nitrogen;
2. Glycine 218 backbone amide nitrogen;
3. Alanine 217 backbone amide nitrogen;
4. Serine 216 backbone amide nitrogen;
5. The side chain carboxylic acid group of aspartic acid 181;
6. The side chain guanidinium group of arginine 47;
7. Arginine 47 backbone amide nitrogen;
8. Aspartic acid 48 backbone amide nitrogen;
9. The side chain hydroxy group of tyrosine 46;
10. The side chain amino group of lysine 41;
11. The methylene side chain atoms of lysine 41;
12. The backbone amide carbonyl of asparagine 44;
13. The methylene side chain atoms of arginine 45;
14. The backbone amide carbonyl of arginine 45;
15. The methylene side chain atoms of arginine 47;
16. The methylene side chain atom of aspartic acid 48;
17. The backbone amide carbonyl of aspartic acid 48;
18. The methylene side chain atoms of leucine 88;
19. The side chain hydroxy group of serine 118;
20. The backbone amide carbonyl of leucine 119;
21. The side chain amide nitrogen of glutamine 262;
22. The side chain atoms of methionine 258;
23. The aromatic group of phenylalanine 52;
24. The backbone amide nitrogen of glycine 259;
25. The alpha-methylene atom of glycine 259;
26. The guanidinium group of arginine 254;
27. The methylene side chain atoms of arginine 254;
28. The methylene side chain atoms of arginine 24;
29. The guanidinium group of arginine 24; or
30. Any conserved water molecule in the vicinity of the active site.
Preferred key structural features of the inhibitors of the present invention include a phosphate isostere (P), a carboxylic acid perferably or a carboxylic acid or ortho-carboxylic acid or o-c acid isostere (B) and a hydrophobic group (A) as shown in Scheme 1.




In a preferred embodiment, the key structural features of the inhibitors of the present invention include a phosphate isostere (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B) and a hydrophobic group (A), preferably a phenyl, naphthyl or thiophenyl as shown in Scheme 1.
In another preferred embodiment the key structural features of the inhibitors of the present invention include an oxalylamide (—NHCOCOOH) (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B) and a hydrophobic group (A).
In another preferred embodiment the key structural features of the inhibitors of the present invention include an oxalylamide (—NHCOCOOH) (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B) and a hydrophobic group (A), preferably a phenyl, naphthyl or thiophenyl as shown in Scheme 1.
In another preferred embodiment the key structural features of the inhibitors of the present invention include a phosphate isostere (P), an ortho-carboxylic acid, or an ortho-carboxylic acid isostere (B), a hydrophobic group (A) and a basic nitrogen (N) as shown in Scheme 2.




In another preferred embodiment, the key structural features of the inhibitors of the present invention include an oxalylamide (—NHCOCOOH) (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), a hydrophobic group (A) and a basic nitrogen (N) as shown in Scheme 2.
In another preferred embodiment, the key structural features of the inhibitors of the present invention include an oxalylamide (—NHCOCOOH) (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), a hydrophobic group (A), preferably a phenyl, naphthyl or thiophenyl and a basic nitrogen (N).
In another preferred embodiment, the key structural features of the inhibitors of the present invention include a basic nitrogen which provides selectivity for PTPases containing an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—a phosphate isostere (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), a hydrophobic group (A) as shown in Scheme 3.




In another preferred embodiment, the key structural features of the inhibitors of the present invention include a basic nitrogen which provides selectivity for PTPases containing an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—an oxalylamide (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), a hydrophobic group (A) as shown in Scheme 3.
In another preferred embodiment, the key structural features of the inhibitors of the present invention include a basic nitrogen which provides selectivity for PTPases containing an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—an oxalylamide (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), and a hydrophobic group (A), preferably a phenyl, naphthyl or thiophenyl as shown in Scheme 3.




In another preferred embodiment, the key structural features of the inhibitors of the present invention include a basic nitrogen which provides selectivity for PTPases containing an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—a phosphate isostere (P), an ortho-carboxylic acid or ortho-carboxylic acid isostere (B), an aromatic group (A), preferably a phenyl or thiophenyl and a hydrophobic group (H) as shown in Scheme 4.
In another preferred embodiment, the key structural features of the inhibitors of the present invention include a basic nitrogen which provides selectivity for PTPases containing an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—an oxalylamide (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), an aromatic group (A), preferably a phenyl or thiophenyl and a hydrophobic group (H) as shown in Scheme 4.
In another preferred embodiment, the key structural features of the inhibitors of the present invention include a phosphate isostere (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), an aromatic group (A), preferably a phenyl or thiophenyl and a hydrophobic group (H) which include a basic nitrogen which provides selectivity for PTPases that contain an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—as shown in Scheme 5.




In another preferred embodiment, the key structural features of the inhibitors of the present invention include an oxalylamide (P), an ortho-carboxylic acid or an ortho-carboxylic acid isostere (B), an aromatic group (A), preferably a phenyl or thiophenyl and a hydrophobic group (H) which include a basic which provides selectivity for PTPases that contain an aspartic acid in position 48—via formation of a salt bridge to said aspartic acid 48 and repulsion to PTPases that contain the corresponding asparagine in position 48—as shown in Scheme 5.
The key structural features of the inhibitors of the present invention described above are linked to each other via covalent bonds.
The compounds of the present invention possess, but are not limited to, a phosphate isostere in which the centroid of the phosphate isostere is 5.0–5.5 Å from the centroid of a carboxylic acid or carboxylic acid isostere, and 4.5–5.1 Å from the centroid of an aromatic group or a hydrophobic group. In a preferred embodiment, the compounds of the present invention possess, but are not limited to, an oxalylamide in which the centroid of the carboxylic acid moiety of said oxalylamide is 5.0–5.5 Å from the centroid of a carboxylic acid or carboxylic acid isostere, and 4.5–5.1 Å from the centroid of an aromatic group or a hydrophobic group.
In an other preferred embodiment the compounds of the present invention possess, but are not limited to, a phosphate isostere in which the centroid of the phosphate isostere is 5.0–5.5 Å from the centroid of a carboxylic acid or carboxylic acid isostere, 4.5–5.1 Å from the centroid of an aromatic group or a hydrophobic group and 8.0–14.0 Å from a basic nitrogen. These features must participate in the appropriate interactions (e.g. hydrogen bonds, salt bridges, hydrophobic interactions, cation-π interactions, or π, π interactions, or aromatic—aromatic interactions) with the PTP1B and/or TC-PTP and/or other PTPases that are structurally similar to PTP1B active site and vicinity e.g. having an aspartic acid (Asp) in position 48. The centroid of the phosphate isostere should be 3.50–4.20 Å from the centroid of the side chain guanidinium group of arginine 221. The centroid of the carboxylic acid or carboxylic acid isostere should be 3.4–4.1 Å from the side chain amino group of lysine 120. The basic nitrogen should be 3.4–4.1 Å from the centroid of aspartic acid 48. The aromatic or, more generally, hydrophobic group should be near the following amino acid side chain atoms with appropriate distance ranges between the centroid of the side chain atoms and the centroid of the aromatic—or hydrophobic group given in parentheses: tyrosine 46 (4.4–5.1 Å) and phenylalanine/histidine 182 (4.4–6.5 Å).
The centroid of the oxalylamide carboxylic acid moiety should be 3.50–4.20 Å from the centroid of the side chain guanidinium group of arginine 221. The centroid of the carboxylic acid or carboxylic acid isostere should be 3.4–4.1 Å from the side chain amino group of lysine 120. The basic nitrogen should be 3.4–4.1 Å from the centroid of aspartic acid 48. The aromatic—or hydrophobic group should be near the following amino acid side chain atoms with appropriate distance ranges between the centroid of the side chain atoms and the centroid of the aromatic—or hydrophobic group given in parentheses: tyrosine 46 (4.4–5.1 Å) and phenylalanine/histidine 182 (4.4–6.5 Å).
In a specific embodiment, the invention is directed to a method of inhibiting at least one intracellular or membrane-associated PTPase that has aspartic acid (Asp) in position 48 using the numbering for PTP1B, the method comprising exposing the PTPase to an inhibitor compound which fits spatially into the active site and the vicinity thereof, said compound comprising the following features and moieties:
I. (a) a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and a hydrogen bond with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.5–4.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å; or (b) an oxalylamide which forms a salt bridge to the guanidinium group of arginine 221 and forms a hydrogen bond with a hydrogen atom donated by the amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the carboxylic acid group of said oxalylamide group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 amide nitrogen ranges from 3.5–4.2 Å and the distance between the amide carbonyl group of said oxalylamide group and the said glycine 220 amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
wherein said acid or said isostere group forms a salt bridge to the side chain amino group of lysine 120 wherein the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said Lysine 120 ranges from 3.4–4.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å;

    
    
        and at least one of features IV through V:
    
    


IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å; and
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å; and

    
    
        one or more of the following features VI–XXXVII:
    
    


VI. an amino group which forms a salt bridge to the site chain carboxylic acid group of aspartic acid 48 such that the distance between the nitrogen atom of said amino group and the centroid of said site chain carboxylic acid group of aspartic acid 48 ranges from 3.4–4.1 Å; and
VII. two oxygen atoms which form hydrogen bonds via a water molecule to the side chain carboxylic acid group of aspartic acid 48 such that the distance between each of the two oxygen atoms and the centroid of said water molecule ranges from 2.5–3.6 Å and that the distance between said water molecule and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 2.5–3.6 Å and that the distance between said two oxygen atoms ranges from 2.5–3.0 Å; and
VIII. a hydrophobic group that interacts with the side chain methylene groups of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the methylene groups of said tyrosine 46 ranges from 4.4–5.1 Å;
IX. a hydrophilic group that forms a hydrogen bond or forms a salt bridge with aspartic acid 181 such that the distance between the centroid of said hydrophilic group and the centroid of the carboxylic acid of said aspartic acid 181 ranges from 4.4–5.1 Å;
X. a hydrophobic group that interacts with tyrosine 46 and the methylene side chain atoms of arginine 47 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 is 4.7–5.2 Å and the centroid of the methylene side chain atoms of said arginine 47 ranges from 4.5–5.5 Å;
XI. a hydrophilic group that forms a hydrogen bond with the one or more hydrogen atoms donated by the guanidinium group of arginine 47 such that the distance between the centroid of said hydrophilic group and the guanidinium group of said arginine 47 ranges from 2.7–3.5 Å;
XII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of arginine 47 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said arginine 47 is 2 ranges from 7–4.0 Å;
XIII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said aspartic acid 48 ranges from 2.7–4.0 Å;
XIV. a hydrophilic group that interacts with the backbone amide carbonyl group of asparagine 44 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said asparagine 44 ranges from 2.7–4.0 Å;
XV. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–40 Å;
XVI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XVII. a hydrophobic group that reaches a proximity interacts with the side chain methylene groups of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XVIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of arginine 45 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said arginine 45 ranges from 2.7–4.0 Å;
XIX. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of tyrosine 46 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said tyrosine 46 ranges from 2.7–4.0 Å;
XX. a hydrophilic group that forms a hydrogen bond with the side chain amino group of lysine 41 such that the distance between the centroid of said hydrophilic group and the amino group of said lysine 41 ranges from 2.7–4.0 Å;
XXI. a hydrophobic group that interacts with the side chain methylene groups of lysine 41 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said lysine 41 ranges from 4.4–5.1 Å;
XXII. a hydrophobic group that interacts with the side chain methylene groups of leucine 88 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said leucine 8 ranges from 4.4–5.1 Å;
XXIII. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of serine 118 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said serine 118 ranges from 2.7–4.0 Å;
XXIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of leucine 119 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said leucine 119 ranges from 2.7–4.0 Å;
XXV. a hydrophilic group that forms a hydrogen bond with the one of the hydrogen atoms donated by the side chain amide nitrogen of glutamine 262 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glutamine 262 ranges from 2.7–4.0 Å;
XXVI. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide group nitrogen of glycine 259 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glycine 259 ranges from 2.7–4.0 Å;
XXVII. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the side chain guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXVIII. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXIX. a hydrophobic group that interacts with the side chain methylene groups of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 254 ranges from 4.4–5.1 Å;
XXX. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXII. a hydrophobic group that interacts with the side chain methylene groups of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XXXIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the backbone amide carbonyl group of said aspartic acid 48 ranges from 2.7–3.5 Å;
XXXIV. a hydrophobic group that interacts with the side chain atoms of methionine 258 such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.5–6.2 Å;
XXXV. a hydrophobic group that interacts with glycine 259 such that the distance between the centroid of said hydrophobic group and the centroid of the alpha-carbon atom of said glycine 259 ranges from 4.5–6.2 Å;
XXXVI. a hydrophobic group that interacts with phenylalanine 52 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic group of said phenylalanine 52 ranges from 4.1–9.1 Å; or
XXXVII. a hydrophobic group that interacts with methionine 258, glycine 259 and phenylalanine 52 being part of a hydrophobic pocket such that the distance between the centroid of said hydrophobic group and (i) the centroid of the side chain of said methionine 258 ranges from 4.1–7.2 Å, (ii) the centroid of said glycine 259 ranges from 4.7–7.7 Å, and (iii) the centroid of the side chain of said phenylalanine 52 ranges from 4.1–9.1 Å;
In another embodiment, the invention provides a method of inhibiting at least one PTPase selected from the group consisting of PTP1B, TC-PTP and other PTPase that are structurally similar to PTP1B comprising exposing said PTPase to a compound that fits spatially into the active site of said PTPase and the vicinity therof, said compound comprising the following features and moieties:
I. (a) a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and interacts with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.5–4.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å; or (b) an oxalylamide which forms a salt bridge to the guanidinium group of arginine 221 and forms a hydrogen bond with a hydrogen atom donated by the amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the carboxylic acid group of said oxalylamide group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 amide nitrogen ranges from 3.5–4.2 Å and the distance between the amide carbonyl group of said oxalylamide group and the said glycine 220 amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
wherein said acid or acid isostere group forms a salt bridge to the side chain amino group of lysine 120 such that the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said lysine 120 ranges from 3.4–4.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å; and

    
    
        one or more of the following features IV and V:
    
    


IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å; and/or
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å; and

    
    
        one or more of the following features VI through XXXVII:
    
    


VI. an amino group which forms a salt bridge to the side chain carboxylic acid group of aspartic acid 48 such that the distance between the nitrogen atom of said amino group and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 3.4–4.1 Å; and
VII. two oxygen atoms which form hydrogen bonds via a water molecule to the side chain carboxylic acid group of aspartic acid 48 such that the distance between each of the two oxygen atoms and the centroid of said water molecule ranges from 2.5–3.6 Å and that the distance between said water molecule and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 2.5–3.6 Å and that the distance between said two oxygen atoms ranges from 2.5–3.0 Å; and
VIII. a hydrophobic group that interacts with the side chain methylene groups of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the methylene groups of said tyrosine 46 ranges from 4.4–5.1 Å;
IX. a hydrophilic group that forms a salt bridge with aspartic acid 181 such that the distance between the centroid of said hydrophilic group and the centroid of the carboxylic acid of said aspartic acid 181 ranges from 4.4–5.1 Å;
X. a hydrophobic group that interacts with tyrosine 46 and the methylene side chain atoms of arginine 47 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.7–5.2 Å and the centroid of the methylene side chain atoms of said arginine 47 ranges from 4.5–5.5 Å;
XI. a hydrophilic group that forms a hydrogen bond with the one or more hydrogen atoms donated by the guanidinium group of arginine 47 such that the distance between the centroid of said hydrophilic group and the guanidinium group of said arginine 47 ranges from 2.7–3.5 Å;
XII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of arginine 47 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said arginine 47 ranges from 2.7–4.0 Å;
XIII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said aspartic acid 48 ranges from 2.7–4.0 Å;
XIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of asparagine 44 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said asparagine 44 ranges from 2.7–4.0 Å;
XV. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XVI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XVII. a hydrophobic group that interacts with the side chain methylene groups of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XVIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of arginine 45 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said arginine 45 ranges from 2.7–4.0 Å;
XIX. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of tyrosine 46 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said tyrosine 46 ranges from 2.7–4.0 Å;
XX. a hydrophilic group that forms a hydrogen bond with the side chain amino group of lysine 41 such that the distance between the centroid of said hydrophilic group and the amino group of said lysine 41 ranges from 2.7–4.0 Å;
XXI. a hydrophobic group that interacts with the side chain methylene groups of lysine 41 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said lysine 41 ranges from 4.4–5.1 Å;
XXII. a hydrophobic group that interacts with the side chain methylene groups of leucine 88 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said leucine 8 ranges from 4.4–5.1 Å;
XXIII. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of serine 118 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said serine 118 ranges from 2.7–4.0 Å;
XXIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of leucine 119 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said leucine 119 ranges from 2.7–4.0 Å;
XXV. a hydrophilic group that forms a hydrogen bond with the one of the hydrogen atoms donated by the side chain amide nitrogen of glutamine 262 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glutamine 262 ranges from 2.7–4.0 Å;
XXVI. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide group nitrogen of glycine 259 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glycine 259 ranges from 2.7–4.0 Å;
XXVII. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the side chain guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXVIII. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXIX. a hydrophobic group that interacts with the side chain methylene groups of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 254 ranges from 4.4–5.1 Å;
XXX. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXII. a hydrophobic group that interacts with the side chain methylene groups of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XXXIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the backbone amide carbonyl group of said aspartic acid 48 ranges from 2.7–3.5 Å;
XXXIV. a hydrophobic group that interacts with the side chain atoms of methionine 258 such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.5–6.2 Å;
XXXV. a hydrophobic group that interacts with glycine 259 such that the distance between the centroid of said hydrophobic group and the centroid of the alpha-carbon atom of said glycine 259 ranges from 4.5–6.2 Å;
XXXVI. a hydrophobic group that interacts with phenylalanine 52 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic group of said phenylalanine 52 ranges from 4.1–9.1 Å;
XXXVII. a hydrophobic group that interacts with methionine 258, glycine 259 and phenylalanine 52 being part of a hydrophobic pocket such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.1–7.2 Å, the centroid of said glycine 259 ranges from 4.7–7.7 Å, and the centroid of the side chain of said phenylalanine 52 ranges from 4.1–9.1 Å;
In yet another embodiment, the invention provides a method of inhibiting a PTPase selected from the group consisting of PTP1B, TC-PTP and other PTPases that are structurally similar to PTP1B comprising exposing said PTPase to a compound that fits spatially into the active site of said PTPase and the vicinity thereof, said compound comprising the following features and moieties:
I. (a) a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and interacts with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.5–4.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å; or (b) an oxalylamide which forms a salt bridge to the guanidinium group of arginine 221 and forms a hydrogen bond with a hydrogen atom donated by the amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the carboxylic acid group of said oxalylamide group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 amide nitrogen ranges from 3.5–4.2 Å and the distance between the amide carbonyl group of said oxalylamide group and the said glycine 220 amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
wherein said acid or said isostere group forms a salt bridge to the side chain amino group of lysine 120 such that the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said Lysine 120 ranges from 3.4–4.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å; and

    
    
        at lest one of the following features IV and V:
    
    


IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 3.55.1 Å; and/or
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 is 4.4–6.5 Å; and one or more of the following features VI–XXXVII
VI. two oxygen atoms which form hydrogen bonds via a water molecule to the side chain carboxylic acid group of aspartic acid 48 such that the distance between each of the two oxygen atoms and the centroid of said water molecule ranges from 2.5–3.6 Å and that the distance between said water molecule and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 2.5–3.6 Å and that the distance between said two oxygen atoms ranges from 2.5–3.0 Å;
VII. an amino group which forms a salt bridge to the side chain carboxylic acid group of aspartic acid 48 such that the distance between the nitrogen atom of said amino group and the centroid of said side chain carboxylic acid group of aspartic acid 48 is 3.4–4.1 Å;
VIII. a hydrophobic group that interacts with the side chain methylene groups of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the methylene groups of said tyrosine 46 ranges from 4.4–5.1 Å;
IX. a hydrophilic group that forms a hydrogen bond with aspartic acid 181 such that the distance between the centroid of said hydrophilic group and the centroid of the carboxylic acid of said aspartic acid 181 ranges from 4.4–5.1 Å;
X. a hydrophobic group that interacts with tyrosine 46 and the methylene side chain atoms of arginine 47 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.7–5.2 Å and the centroid of the methylene side chain atoms of said arginine 47 ranges from 4.5–5.5 Å;
XI. a hydrophilic group that forms a hydrogen bond with the one or more hydrogen atoms donated by the guanidinium group of arginine 47 such that the distance between the centroid of said hydrophilic group and the guanidinium group of said arginine 47 ranges from 2.7–3.5 Å;
XII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of arginine 47 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said arginine 47 ranges from 2.7–4.0 Å;
XIII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said aspartic acid 48 ranges from 2.7–4.0 Å;
XIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of asparagine 44 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said asparagine 44 ranges from 2.7–4.0 Å;
XV. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XVI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XVII. a hydrophobic group that interacts with the side chain methylene groups of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XVIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of arginine 45 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said arginine 45 ranges from 2.7–4.0 Å;
XIX. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of tyrosine 46 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said tyrosine 46 ranges from 2.7–4.0 Å;
XX. a hydrophilic group that forms a hydrogen bond with the side chain amino group of lysine 41 such that the distance between the centroid of said hydrophilic group and the amino group of said lysine 41 ranges from 2.7–4.0 Å;
XXI. a hydrophobic group that interacts with the side chain methylene groups of lysine 41 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said lysine 41 ranges from 4.4–5.1 Å;
XXII. a hydrophobic group that interacts with the side chain methylene groups of leucine 88 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said leucine 8 ranges from 4.4–5.1 Å;
XXIII. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of serine 118 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said serine 118 ranges from 2.7–4.0 Å;
XXIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of leucine 119 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said leucine 119 ranges from 2.7–4.0 Å;
XXV. a hydrophilic group that forms a hydrogen bond with the one of the hydrogen atoms donated by the side chain amide nitrogen of glutamine 262 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glutamine 262 ranges from 2.7–4.0 Å;
XXVI. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide group nitrogen of glycine 259 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glycine 259 ranges from 2.7–4.0 Å;
XXVII. a hydrophilic group that forms a hydrogen-bond with one or more hydrogen atoms donated by the side chain guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXVIII. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXIX. a hydrophobic group that interacts with the side chain methylene groups of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 254 ranges from 4.4–5.1 Å;
XXX. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXII. a hydrophobic group that interacts with the side chain methylene groups of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XXXIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the backbone amide carbonyl group of said aspartic acid 48 ranges from 2.7–3.5 Å;
XXXIV. a hydrophobic group that interacts with the side chain atoms of methionine 258 such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.5–6.2 Å;
XXXV. a hydrophobic group that interacts with glycine 259 such that the distance between the centroid of said hydrophobic group and the centroid of the alpha-carbon atom of said glycine 259 ranges from 4.5–6.2 Å;
XXXVI. a hydrophobic group that interacts with phenylalanine 52 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic group of said phenylalanine 52 ranges from 4.1–9.1 Å; or
XXXVII. a hydrophobic group that interacts with methionine 258, glycine 259 and phenylalanine 52 being part of a hydrophobic pocket such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.1–7.2 Å, the centroid of said glycine 259 is 4.7–7.7 Å, and the centroid of the side chain of said phenylalanine 52 ranges from 4.1–9.1 Å;
Further provided is a method of inhibiting at least one PTPase selected from the group consisting of Protein Tyrosine Phosphatase 1B (PTP1B) and/or T-Cell Protein Tyrosine Phosphatase which (TC-PTP) and/or other PTPases that are structurally similar to PTP1B comprising exposing said PTPase to a compound that fits spatially into the active site of said PTPase and the vicinity thereof, said compound comprising:
I. (a) a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and forms a hydrogen bond with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.54.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å; or (b) an oxalylamide which forms a salt bridge to the guanidinium group of arginine 221 and forms a hydrogen bond with a hydrogen atom donated by the amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the carboxylic acid group of said oxalylamide group and (1) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 amide nitrogen ranges from 3.54.2 Å and the distance between the amide carbonyl group of said oxalylamide group and the said glycine 220 amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
wherein said acid or isostere group forms a salt bridge to the side chain amino group of lysine 120 such that the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said lysine 120 ranges from 3.44.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å; and at least one of the following features IV and V:
IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å; or
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å.
In another specific embodiment, the invention provides a method of inhibiting at least one PTPase selected from the group consisting of Protein Tyrosine Phosphatase 1B (PTP1B), T-Cell Protein Tyrosine Phosphatase (TC-PTP) and other PTPases that are structurally similar to PTP1B which comprises exposing said PTPase to a compound that fits spatially into the active site of said PTPase and the vicinity thereof, said compound comprising:
I. a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and interacts with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.5–4.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
wherein said acid or isostere group forms a salt bridge to the side chain amino group of lysine 120 such that the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said lysine 120 ranges from 3.4–4.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å; and
IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å; or
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å;
wherein the distance between the centroid of the phosphate isostere and the centroid of (I) said carboxylic acid or carboxylic acid isostere ranges from 4.9–5.9 Å, (II) said amino group ranges from 8.0–14.0 Å and between the centroid of said carboxylic acid or carboxylic acid isostere and said amino group ranges from 4.8–5.8 Å or
wherein the distance between the centroid of the phosphate isostere and the centroid of (I) said carboxylic acid or carboxylic acid isostere ranges from 4.9–5.9 Å, (II) said oxygen atoms are ranges from 8.0–14.0 Å and between the centroid of said carboxylic acid or carboxylic acid isostere and said oxygen atoms are ranges from 5.0–7.9 Å.
The invention further provides a method of inhibiting at least one PTPase selected from the group consisting of Protein Tyrosine Phosphatase 1B (PTP1B), T-Cell Protein Tyrosine Phosphatase (TC-PTP) and other PTPases that are structurally similar to PTP1B which comprises exposing said PTPase to a compound that fits spatially into the active site of said PTPase and the vicinity thereof, said compound comprising:
I. an oxalylamide which forms a salt bridge to the guanidinium group of arginine 221 and forms a hydrogen bond with a hydrogen atom donated by the amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the carboxylic acid group of said oxalylamide group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 amide nitrogen ranges from 3.5–4.2 Å and the distance between the amide carbonyl group of said oxalylamide group and the said glycine 220 amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
wherein said acid or isostere group forms a salt bridge to the side chain amino group of lysine 120 such that the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said lysine 120 ranges from 3.4–4.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å; and
IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å; or
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å; and
wherein the distance between the centroid of the carboxylic acid group of said oxalylamide group and the centroid of (I) said carboxylic acid or carboxylic acid isostere ranges from 4.9–5.9 Å, (II) said amino group ranges from 8.0–14.0 Å and between the centroid of said carboxylic acid or carboxylic acid isostere and said amino group ranges from 4.8–5.8 Å or
wherein the distance between the centroid of the carboxylic acid group of said oxalylamide group and the centroid of (I) said carboxylic acid or carboxylic acid isostere ranges from 4.9–5.9 Å, (II) said oxygen atoms are ranges from 8.0–14.0 Å and between the centroid of said carboxylic acid or carboxylic acid isostere and said oxygen atoms are ranges from 5.0–7.9 Å.
The hydrophobic groups that interact with tyrosine 46 and phenylalanine/histidine 182 include, but are not limited to, alkyl and aryl groups. These hydrophobic groups include cyclohexyl, phenyl, naphthyl, thiophenyl, pyrrolyl and furanyl. The hydrophobic groups that interact with one or more of the tyrosine 46 and the arginines 24, 45, 47, and 254 include, but are not limited to, alkyl and aryl groups. These hydrophobic groups include cyclohexyl, phenyl, naphthyl, thiophenyl, pyrrolyl and furanyl, optionally substituted The hydrophobic groups that interact with methionine 258, glycine 259 and phenylalanine 52 include, but are not limited to, alkyl and aryl groups groups. These aryl groups include phenyl, thiophenyl, pyrrolyl, furanyl, C1–C6alkyl and arylC1–C6alkyl which are defined hereinbelow.
The hydrophilic groups that interact with the hydrogen atom donated by the side chain amide nitrogen of arginine 47, aspartic acid 48, leucine 119, glycine 259, lysine 41, lysine 120, the side chain amide hydrogen atom donated by glutamine 262, the hydrogen atoms donated by the guanidinium group of arginine 254, arginine 45 or arginine 24 include, but are not limited to, hydroxy, C1–C6alkyloxy, aminocarbonyl, oxo, SO, SO2, SONH2, SO2NH2, SO2NHCF3, COOH or a group selected from the following 5-membered heterocycles




The hydrophilic groups that interact with the side chain amide carbonyl group of asparagine 44, arginine 45 or aspartic acid 48 include, but are not limited to, amino, aminocarbonyl, hydroxy, SONH2, SO2NH2, or SO2NHCF3.
The hydrophilic groups that interact with the side chain carboxylic acid group of aspartic acid 181 include, but are not limited to, amino, aminocarbonyl, hydroxy, C1–C6alkyloxy, SONH2, SO2NH2. The hydrophilic groups that interact with the side chain hydroxy group of serine 118 include, but are not limited to, aminocarbonyl, hydroxy, C1–C6alkyloxy, SONH2, SO2NH2.
Unique Structural Elements in PTP1B
To identify unique residues or combinations of residues of PTP1B that could be utilised as points of interaction by selective inhibitors, alignment of the primary sequences of the catalytic domains of approximately 105 known vertebrate PTPases (Andersen, J. N. et al., (1999) in preparation) was done (Table 1, below). Using the crystal structure of PTP1B (Andersen, H. S. et al. (1999) J. Biol. Chem. 275:7107–7108 (2000); Barford, D., et al. Science 263:1397–1404 (1994)), unique combinations of residues in the active site pocket or in its vicinity were identified, i.e. in a distance (3–5.5 Å) that would allow simultaneous binding to the active site and these residues, while still retaining a low molecular weight (for example, below 700 dalton). In particular, the combination of 4 residues seems unique for the PTP1B family: arginine 47, aspartic acid 48, methionine 258, and glycine 259 arginine 47 and aspartic acid 48 contribute significantly to the binding of peptide substrates in PTP1B (Jia, Z. C., et al., Science 268:1754–1758 (1995)). A comparison of these regions in representative members of 14 PTP families, indicates that in particular residue 48 is an attractive binding element for selective PTP1B ligands since this residues is an aspartic acid in PTP1B and an asparagine in many other PTPases. Aspartic acid 48 is well-defined in the published PTP1B structures ((Puius, Y. A. et al. Proc. Natl. Acad. Sci. USA 94:13420–13420 (1997)), (Pannifer, A. D. B., et al., J. Biol. Chem. 273:10454–10462 (1998)) and it is believed to play an important role in positioning substrates correctly relative to the active site (Sarmiento, M., et al., J. Biol. Chem. 273: 26368–26374 (1998)).







TABLE 1







Non-limiting examples of selected amino acid residues at positions


in the vicinity of the active site (single letter code - PTP1B


numbering)





















Residue
PTP1B
SHP1
PTP-L1
PTPD2
PTPH1
STEP
IA-2
PTPβ
PTPα
PTPε
PTP-LAR
PTPμ
CD45
PTPχ
























47
R
K
K
R
K
K
P
N
V
P
A
G
V
I


48
D
N
N
E
D
T
D
N
N
N
N
N
D
N


258
M
S
H
M
A
G
P
V
C
P
N
V
C
N


259
G
G
G
F
M
G
G
H
Q
Q
Y
N
L
Y









Optimization for Potency

The key structural features of 2-(oxalyl-amino)-benzoic acid (OBA) are the two carboxy groups respectively bound—directly and through a carbonylamino group—to an aromatic ring. Replacement of the phenyl ring in OBA by thiophene, resulted in compounds with little difference in potency between the regioisomer 2-aminothiophene and 3-aminothiophene.
Previous studies have shown that phenyl-based phosphonate inhibitors have little affinity for PTP1B, while addition of a second phenyl ring (e.g. [(1,1-difluoro-1-naphthalenyl)-methyl]phosphonic acid) significantly increased the potency (Burke, T. R. et al., Biochemistry 35:15989–15996 (1996)). The enhanced potency of the naphthalene ring system is due to extensive hydrophobic interactions with the side chains of tyrosine 46, valine 49, phenylalanine 182, alanine 217 and isoleucine 219. Similarly, 3-(oxalyl-amino)-naphthalene-2-carboxylic acid interacts with the same residues. It was reasoned that a saturated ring fused to 2-(oxalyl-amino)-thiophene-3-carboxylic acid (2-OTA) and/or 3-(oxalyl-amino)-thiophene-2-carboxylic acid (3-OTA) would serve a similar function and increase the potency. Further, the proposed binding mode of such a compound should bring the saturated ring in close proximity to residues arginine 47 and aspartic acid 48. Introducing a basic nitrogen or polar changes in this saturated ring would allow further interactions with the side chains or backbone amides of arginine 47 and aspartic acid 48. In accordance with the above alignment studies, we anticipated that selectivity for PTP1B and other PTPases with an aspartic acid in position 48 could be obtained by specifically addressing this area of the enzyme.
Consequently, 2-(oxalyl-amino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid (2-OBTA) was synthesised and its potency analysed against a set of PTPases. Table II shows that 2-OBTA is about 10-fold more potent against PTP1B than compounds 3-OTA and 2-OTA and 3-fold more potent than OBA when tested at pH 5.5 (the pH optimum for PTP1B using pNPP as substrate). Further, the inhibitory profile against this set of PTPases is almost the same as that of 3-(oxalyl-amino)-naphthalene-2-carboxylic acid. Thus, although 2-OBTA retains the features of a general PTP inhibitor, it already shows some selectivity for PTP1B. These results clearly indicate that 2-OBTA spatially fits in this region of PTP1B. Various substitutions in the saturated ring of 2-OBTA were found to influence the binding affinities for different PTPases (not shown).







TABLE 2







Ki values (μM) - pH 5.5














OBA
3-OTA
2-OTA
2-OBTA
2-OTPyA
2-OTPA
















PTP1B
20
61
62
5.7
0.3
15


SHP-1
530
>2000
60
120
900
350


PTPα
700
500
1700
300
>2000
270


D1


PTPε
125
350
590
45
600
20


D1


PTPβ
32
160
18
14
150
12


CD45
160
250
70
40
110
50


D1D2


LAR
>2000
>2000
>2000
400
>2000
360


D1D2









As indicated above, in comparison with OBA, 2-OBTA showed an approximately 3-fold increase in affinity for most PTPases. It was hypothesised that the saturated ring of 2-OBTA would occupy almost the same position as the distal ring of 3-(oxalyl-amino)-naphthalene-2-carboxylic acid, which was previously shown to bind in the proximity of arginine 47 and aspartic acid 48. Therefore, as expected, there was no apparent change in selectivity in accordance with the notion that the saturated ring makes hydrophobic contact with conserved residues such as tyrosine 46, alanine 217, valine/isoleucine219 and isoleucine/valine 49 (PTP1B numbering).
Optimization for Selectivity
The combination of arginine 47 and aspartic acid 48 offers a rather unique, selective ligand-binding region in PTP1B. The side chains of both residues are charged at neutral pH and are therefore sutiable for salt bridge formation. Introducing a positive charge in 2-OBTA that could form a salt bridge with aspartic acid 48, would not only increase the potency of 20BTA against PTP1B but also—due to repulsive forces between the positive ligand charge and the asparagine side chain found in many other PTPases—decrease the affinity of 20 BTA for these PTPases.
Three side chain rotamer conformations are normally defined for an aspartic acid residue (rota 1: 47.7%, rota 2: 33.6% and rota 3: 15.9%). In the published X-ray structures of PTP1B, two rotamers have been described, rota 1 and 3. The rota 3 conformation is stabilised by an internal hydrogen bond between the side chain and main chain amide with the side chain bending towards the active site pocket. Further, rota 3 seems to be the preferred rotamer for aspartic acid 48. The rota 1 conformation has only been found in four of the eleven published X-ray structures, and in three of these cases the rota 1 position is necessitated due to ligand occupancy. The aspartic acid 48 rota 1 conformation is pointing away from the active site pocket. Thus, rota 3 was found both in the apo-enzyme and in PTP1B complexed with peptide ligands that seem to stabilize this conformation. Further, we have recently co-crystallized PTP1B with OBA and 3 derivatives and found aspartic acid 48 in the rota 3 position in all structures (Andersen, H. S. et al. J. Biol. Chem. 275, 7101–7108 (2000)). Based on these observations, it was hypothesized that introduction of a basic nitrogen in the saturated ring in 2-OBTA would be sufficiently close to aspartic acid 48 to allow the formation of a salt bridge. A recent survey of 322 unrelated proteins has shown that aspartic acid and asparagine residues have a strong tendency to form hydrogen bonds with neighboring backbone amides and in both cases with a significant preference for internal hydrogen bonds.
Assuming that asparagine 48 of other PTPases, e.g. PTPα, forms an internal hydrogen bond similar to that observed for aspartic acid 48 in PTP1B, the side chain amide of the asparagine with its positive dipole would be in an unfavourable position to the proposed basic nitrogen and thus cause repulsion.
2-(Oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid (2-OTPyA)—containing a positively charged tetrahydropyridine ring (pKa>10)—was synthesised in order to test the foregoing hypothesis. In agreement with the predictions, the affinity for PTP1B was increased about 20-fold without any significant increase in molecular weight (Table 2). Further, this compound showed an almost astonishing selectivity for PTP1B versus all other PTPases tested. Again, this is in agreement with the hypothesis that repulsive forces between the basic nitrogen in 2-OTPyA and the positive dipole of the asparagine side chain decrease the potency against other PTPases. CD45, which also contains an aspartic acid in position 48, is a noticeable exception showing only a 2-fold decrease. It is speculated that the preferred rotamer of aspartic acid 48 in CD45 is the rota 1 conformation, which is too far away for salt bridge formation with 2-OTPyA. In addition, CD45 contains a valine in position 47, which may not have the same influence on aspartic acid 48 as an arginine.
2-(Oxalyl-amino)-4,7-dihydro-thieno[2,3-c]pyran-3-carboxylic acid (2-OTPA)—containing a negative dipole in the dihydropyran ring—was synthesised. In agreement with the predictions, the affinity for PTP1B was decreased about 2.5-fold compared to 2-OBTA without any significant increase in molecular weight (Table 2).
Table A (at the end of the specification) discloses the protein coordinates of PTP1B complexed with 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid (2-OTPA) and in FIG. 1 is the active site of PTP1B complexed with 2-OTPA shown.
Optimization for Potency Towards Arginine 47 and Aspartic Acid 48
Using further the combination of the 4 unique residues for the PTP1B family: arginine 47, aspartic acid 48, methionine 258, and glycine 259 it was hypothesised that an increase in potency could be obtained by introduction of a hydrogen-bond acceptor side chain that could form one or more hydrogen bonds with the main chain amides of arginine 47 and aspartic acid 48, would increase the potency against PTP1B. 5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid (5-HTPyA) (Example 52)—still containing a positively charged tetrahydropyridine ring and three hydrogen-bond acceptors (oxygen atoms)—was synthesised. In agreement with the predictions, the affinity for PTP1B was increased about 13-fold compared to 2-OTPyA.
Changing the positively charged nitrogen atom with a non charged oxygen atom and still addressing the main chain amides of arginine 47 and aspartic acid 48, it was hypothesised that an increase in general potency could be obtained. Thus, 5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (5-HTPA) (Example 4)—containing a non charged dihydropyran ring and three hydrogen-bond acceptor oxygen atoms—was synthesised. In agreement with the predictions, only the general potency was increased compared to 2-OTPyA as shown in Table 3.
Selectivity Via Steric Hindrance
Referring again to the combination of the 4 residues unique for the PTP1B family: arginine 47, aspartic acid 48, methionine 258, and glycine 259, but this time more specifically to the combination of methionine 258 and glycine 259, which form part of a hydrophobic pocket in PTP1B in contrast to most other PTPases where the pocket is filled out: PTPα: cysteine 258-glutamine 259; PTP β: valine 258-histidine 259; PTP-LAR: asparagine 258-tyrosine 259; and CD45: cysteine 258-leucine 259 (PTP1B numbering), it was hypothesised that an increase in potency and selectivity could be obtained by introduction of a hydrophobic side chain that could form hydrophobic interactions to glycine 259 and to the side chain of methionine 258 and at the same time take part in repulsion-/steric hindrance with the same residues in other PTPases. Thus, 7-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (7-MOTPA) (Example 26)—containing a hydrophobic 1,3-dihydro-isoindol side chain—was synthesised. In agreement with the predictions, both affinity and selectivity for PTP1B was increased as shown in Table 3 compared to 2-OTPA.







TABLE 3







Ki values (μM) - pH 7













2-OTPA
7-MOTPA
5-HTPA
















PTP1B
63
1.2
1.9



PTPα D1
1100
620
93



PTPε D1
290
330
11



PTPβ
17
8.9
1.1



CD45 D1D2
960
380
130










Table B (at the end of the specification) discloses the protein coordinates of PTP 1B complexed with 7-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (7-MOTPA) (Example 26), and FIG. 2 shows the crystal structure of the active site of PTP1B complexed with 7-MOTPA.
Table C (at the end of the specification) discloses the protein coordinates of PTP1B complexed with 5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (5-HTPA) (Example 4), and FIG. 3 shows the crystal structure of the active site of PTP1B complexed with 5-HTPA.
Table D (at the end of the specification) discloses the protein coordinates of PTP1B complexed with 2-(oxalyl-amino)-7-(1,1,3-trioxo-1H-benzo [d]isothiazol-3-yloxomethyl)-4,7-dihydro-5H, thieno[2,3-c]pyran-3-carboxylic acid (example 54), including key water molecules. FIG. 2 is the active site with selected water molecules shown.
Specific interactions of certain inhibitors of the present invention at the active site of PTP1B are detailed below.
The carboxy group of the oxamicN acid of 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid is positioned 2.9–3.0 Å from the guanidinium group of arginine 221 forming a salt bridge, as well as a hydrogen bond with the main chain amide of arginine 221 and serine 216, and the carbonyl forms a hydrogen bond with the main chain amide of glycine 220. The carboxy group in the 3 position is positioned 2.8 Å from lysine 120 forming a salt bridge. The tetrahydro-thieno[2,3-c]pyridine ring forms hydrophobic interactions with phenylalanine 182, tyrosine 46, valine 49, alanine 217 and isoleucine 219. The basic nitrogen in the tetrahydro-thieno[2,3-c]pyridine ring is positioned 2.8 Å from the carboxy group of aspartic acid 48 forming a salt bridge.
The carboxy group of the oxamic acid of 7-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-thieno[2,3-c]pyran-3-carboxylic acid (Example 26) is positioned 2.9–3.0 Å from the guanidinium group of arginine 221 forming a salt bridge, as well as a hydrogen bond with the main chain amide of arginine 221 and serine 216, and the carbonyl forms a hydrogen bond with the main chain amide of glycine 220. The carboxy group in the 3 position is positioned 2.8 Å from lysine 120 forming a salt bridge. The dihydro-thieno[2,3-c]pyran ring forms hydrophobic interactions with phenylalanine 182, tyrosine 46, valine 49, alanine 217 and isoleucine 219. The phenyl ring of the isoindol ring forms a hydrophobic interaction with the side chain methylene atom of aspartic acid 48 and the 5-methoxy substituent forms hydrophobic interactions with the side chain atoms of methionine 258.
The carboxy group of the oxamic acid of 5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-thieno[2,3-c]pyran-3-carboxylic acid (Example 4) is positioned 2.9–3.0 Å from the guanidinium group of arginine 221 forming a salt bridge, as well as a hydrogen bond with the main chain amide of arginine 221 and serine 216, and the carbonyl forms a hydrogen bond with the main chain amide of glycine 220. The the carboxy group in the 3 position is positioned 2.7 Å from lysine 120 forming a salt bridge. The dihydro-thieno[2,3-c]pyran ring forms hydrophobic interactions with phenylalanine 182, tyrosine 46, valine 49, alanine 217 and isoleucine 219. The side chain methylene group at the 5 position of the thieno[2,3-c]pyran forms a hydrophobic interaction the side chain methylene group of aspartic acid 48. The phenyl ring of the isoindol ring forms a hydrophobic interaction with tyrosine 46 and both one of the oxo atoms and the hydroxy group at the isoindole forms hydrogen bonds respectively with the main chain amide of aspartic acid 48 and arginine 47.
To further substantiate the generality in using steric hindrance/steric fit to obtain selectivity for PTP1B, TC-PTP and structurally similar PTPases we also synthesized 7-(1,1-dioxo-1H-benzo[d]isothiazol-3-yloxymethyl)-2-(oxalyl-amino)-4,7-dihyd ro-5H-thieno[2,3-c]pyran-3-carboxylic acid (“Compound N”). The substitution was introduced in the 7-position to address the region defined by residues 258 and 259. As indicated above, this part of PTP1B forms a hydrophobic pocket with direct access to the active site, whereas the same region is sterically hindered by more bulky side chains, in particular those corresponding to residue 259 in PTP1B. Compound N was synthesized with a substituent in the 7-position of 2-OTPA to sterically fit with this part of PTP1B and TC-PTP, but cause steric hindrance in other PTPs.
To test directly, whether the above compound was addressing the proposed region of PTP1B, Compound N was subjected to detailed enzyme kinetic analyses using a set of wildtype (wt) and mutant PTPs. Two enzymes, PTPα and PTPH1, were chosen as representatives for PTPs with bulky side chains in the 259 position. Using a combination of wt and PTP mutants it has previously been shown that Gln259 in PTPα, in addition to its direct effect, also indirectly influences the binding of inhibitors and substrates, most likely due to a negative influence on the rotational freedom of the side chain of Gln262 (Peters et al., J. Biol. Chem. 275: 18201–18209 (2000)). As described above, selectivity can be obtained by introducing a basic nitrogen into 2-(oxalylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid that causes attraction in PTP1B due to salt bridge formation to Asp48 and repulsion against PTPs with an asparagine in the 48 position, such as PTPα. To analyze if the current approach based on steric hindrance is generally applicable, it was decided to include a PTP with an aspartic acid in position 48. PTPH1, which like PTP1B is an intracellular enzyme with one domain only, was selected for these studies. The results of these studies are shown below (Table 4).










TABLE 4







Enzyme
Ki values (μM) at pH 7.0



















PTP1B wt
0.4



PTP1B G259Q
65



PTP1B G259M
55



PTPα wt
>500



PTPα Q259G
70



PTPH1 wt
55



PTPH1 M259G
12










It appears that introduction of bulky side chains in the 259 position in PTP1B causes a very significant decrease in affinity for NNC 52–1153. Conversely, replacement of the bulky residues in PTPα and PTPH1 with a glycine increases the affinity. This clearly indicates that NNC 52–1153 addresses the 258–259 region of PTP1B.
Specificity against a broad set of PTPs—It was next analyzed if the side chain of NNC 52–1153 would cause the increased selectivity against other PTPs. NNC 52–1153 was tested against a set of 10 different wt PTP domains (Table 5). It appears from this table that a substantial increase in affinity for PTP1B and TC-PTP has been obtained, while at the same time introducing a very high degree of selectivity against many other PTPs representing a broad spectrum of this class of enzymes (having Asp 48).










TABLE 5







Enzyme
Ki values (μM) at pH 7.0



















PTP1B
0.4



TC-PTP
0.6



PTPH1
55



PTPα
700



PTPε
460



CD45
500



LAR
120



GLEPP1
150



PTPβ
15










To unequivocally determine the binding mode, x-ray co-crystallization studies of PTP1B and NNC 52–1153 were initiated. A well-suited electron density was identified in the active site pocket. The oxalylamino and o-carboxy groups show the exact same interaction with the PTP signature motif and salt bridge formation to Lys120 as described previously for 2-(oxalylamino)-benzoic acid and the thiophene-based derivatives. Significantly, the side chain of the ligand is positioned in close vicinity to residues 258 and 259. Several interaction points appear to be responsible for the observed significant increase in affinity for PTP1B. Thus, a long hydrogen bond seems to interact with one carbonyl of the ligand side chain. In addition, important van der Waals contacts are made between the aromatic ring of the ligand side chain and the side chain of Met248 and Cβ atom of Asp48.

As described above, we have utilized salt bridge formation to Asp48 to obtain potent and selective PTP1B inhibitors. In these structures, Asp48 was in the so-called rotamer (“rota”) 3 position—pointing towards the active site. In contrast, the side chain of Asp48 is pushed away from the active site by the oxygen molecules in NNC 52–1153 (i.e. the rotamer 1 position). This allows a novel water molecule to form a bridge between the two oxygen molecules in the ligand and Asp48. This surprising observation can be used to design additional inhibitors of PTP1B.
The present invention encompasses, but is not limited to, compounds of the Formula 1 wherein n, m, X, Y, R1, R2, R3, R4, R5 and R6 are defined below;




In the above Formula 1
n is 0, 1 or 2 (if m=0 then n is 1 or 2);
m is 0, 1 or 2 (if n=0 then m is 1 or 2);
X is S, O, NR8;
Y is NR7, O, S, SO, SO2;
R1 is hydrogen, COOR3, or selected from the following 5-membered heterocycles:




R2 is hydrogen, C1–C6alkyl, hydroxy, NR9R10;

R3 is hydrogen, C1–C6alkyl, arylC1–C6alkyl, C1–C6alkylcarbonyloxylC1–C6alkyl, C1–C6alkylcarbonyloxyarylC1–C6alkyl;

R4, R5 and R6 are independently hydrogen, trihalomethyl, C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, carboxy, carboxyC1–C6alkyl, C1–C6alkyloxy-carbonyl, aryloxycarbonyl, arylC1–C6alkyloxycarbonyl, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxy, aryloxy C1–C6 alkyl, arylC1–C6alkyloxy, arylC1–C6alkyloxyC1–C6alkyl, thio, C1–C6alkylthio, C1–C6alkylthioC1–C6alkyl, arylthio, arylC1–C6alkylthio, arylC1–C6alkylthioC1–C6alkyl, NR9R10, C1–C6alkylaminoC1–C6alkyl, arylC1–C6alkylaminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarbonylC1–C6alkyl, arylC1–C6alkylcarbonyl, arylC1–C6alkylcarbonylC1–C6alkyl, C1–C6alkylcarboxy, C1–C6alkylcarboxyC1–C6-alkyl, arylcarboxy, arylcarboxyC1–C6alkyl, arylC1–C6alkylcarboxy, arylC1–C6alkylcarboxyC1–C6alkyl, C1–C6alkylcarbonylamino, C1–C6alkylcarbonyl-aminoC1–C6alkyl, -carbonylNR7C1–C6alkylCOR13, arylC1–C6alkylcarbonyl-amino, arylC1–C6alkylcarbonylaminoC1–C6alkyl, arylamino carbonylaminoC1–C6 alkyl, arylaminoC1–C6 alkyl, arylcarbonylamino C1–C6 alkyl, CONR9R10, R8R9NC1–C6 alkyl, or C1–C6alkyl-CONR9R10 wherein the alkyl and aryl groups are optionally substituted and R13 is NR9R10, or C1–C6alkylNR9R10; R7 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkyloxocarbonyl, arylcarbonyl, aryloxocarbonyl, arylC1–C6alkylcarbonyl, arylC1–C6alkyloxocarbonyl, C1–C6alkylcarboxy, arylC1–C6alkylcarboxy, R9R10NcarbonylC1–C6alkyl wherein R9 and R0 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy; wherein the alkyl and aryl groups are optionally substituted;

R8 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy wherein the alkyl and aryl groups are optionally substituted;

R9 and R10 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy wherein the alkyl and aryl groups are optionally substituted; or

R9 and R10 are together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system can optionally be substituted with at least one C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, C1–C6alkyloxy, arylC1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, NR11R12 or C1–C6alkylamino-C1–C6alkyl, wherein R11 and R12 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy; wherein the alkyl and aryl groups are optionally substituted; or

R9 and R10 are independently a saturated or partial saturated cyclic 5, 6 or 7 membered amine, imide or lactam or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.

The compounds of Formula 1 are oxalylamide compounds having in common key structural features required of non hydrolysable protein tyrosine phosphatase inhibitors, most particularly PTP1B and/or TC-PTP inhibitors. These structural features endow the present compounds with the appropriate molecular shape necessary to fit into the enzymatic active site, to bind to such site in a non covalently way, thereby blocking the site and inhibiting enzymatic biological activity. Referring to Formula 1, such structural features include the oxalylamide and an ortho-carboxylic acid attached to a hydrophobic group, preferably an aryl as defined below The compounds of the invention can be further modified to act as pro-drugs.
It is a well known problem in drug discovery that compounds, such as enzyme inhibitors, may be very potent and selective in biochemical assays, yet be inactive in vivo. This lack of so-called bioavailability may be ascribed to a number of different factors such as lack of or poor absorption in the gut, first pass metabolism in the liver, poor uptake in cells. Although the factors determining bioavailability are not completely understood, there are many examples in the scientific literature—well known to those skilled in the art—of how to modify compounds, which are potent and selective in biochemical assays but show low or no activity in vivo, into drugs that are biologically active. It is within the scope of the invention to modify the compounds of the invention, termed the ‘original compound’ or “prototype”, by attaching chemical groups that will improve the bioavailability of said compounds in such a way that the uptake in cells or mammals is facilitated. Examples of said modifications, which are not intended in any way to limit the scope of the invention, include changing of one or more carboxy groups to esters (for instance methyl esters, ethyl esters, acetoxymethyl esters or other acyloxymethyl esters). Compounds of the invention, original compounds, modified by attaching chemical groups are termed ‘modified compounds’ Said chemical groups may or may not be apparent in the claims of this invention. Other examples of modified compounds, which are not intended in any way to limit the scope of the invention, are compounds that have been cyclized at specific positions—so called ‘cyclic compounds’—which upon uptake in cells or mammals become hydrolyzed at the same specific position(s) in the molecule to yield the compounds of the invention, the original compounds, which are then said to be ‘non-cyclic’ For the avoidance of doubt, it is understood that the latter original compounds in most cases will contain other cyclic or heterocyclic structures that will not be hydrolyzed after uptake in cells or mammals. Generally, said modified compounds will not show a behavior in biochemical assays similar to that of the original compound, i.e. the corresponding compounds of the invention without the attached chemical groups or said modifications. Said modified compounds may even be inactive in biochemical assays. However, after uptake in cells or mammals these attached chemical groups of the modified compounds may in turn be removed spontaneously or by endogenous enzymes or enzyme systems to yield compounds of the invention, original compounds. ‘Uptake’ is defined as any process that will lead to a substantial concentration of the compound inside cells or in mammals. After uptake in cells or mammals and after removal of said attached chemical group or hydrolysis of said cyclic compound, the compounds may have the same structure as the original compounds and thereby regain their activity and hence become active in cells and/or in vivo after uptake. A number of procedures, well known to those skilled in the art, may be used to verify that the attached chemical groups have been removed or that the cyclic compound has been hydrolyzed after uptake in cells or mammals. An example, which is not intended in any way to limit the scope of the invention, is given in the following. A mammalian cell line, which can be obtained from the American Tissue Type Collection or other similar governmental or commercial sources, is incubated with said modified compound. After incubation at conditions well known to those skilled in the art, the cells are washed appropriately, lysed and the lysate is isolated. Appropriate controls, well known to those skilled in the art, must be included. A number of different procedures, well known to those skilled in the art, may in turn be used to extract and purify said compound from said lysate. Said compound may or may not retain the attached chemical group or said cyclic compound may or may not have been hydrolyzed. Similarly, a number of different procedures—well known to those skilled in the art—may be used to characterize said purified compound structurally and chemically. Since said purified compound has been isolated from said cell lysate and hence has been taken up by said cell line, a comparison of said structurally and chemically characterized compound with that of the original unmodified compound (i.e. without said attached chemical group or said non-cyclic compound) will immediately provide to those skilled in the art information on whether the attached chemical group as been removed in the cell or whether the cyclic compound has been hydrolyzed. As a further analysis, said purified compound may be subjected to enzyme kinetic analysis as described in detail in the present invention. If the kinetic profile is similar to that of the original compound without said attached chemical group, but different from said modified compound, this confirms that said chemical group has been removed or said cyclic compounds has been hydrolyzed. Similar techniques may be used to analyze compounds of the invention in whole animals and mammals.
Preferred prodrug classes for the present compounds include acyloxymethyl esters or acyloxymethyl carbamates of the compounds of the present invention which may be prepared by the following general, procedure (C. Schultz et al, J. Biol. Chem., 1993, 268, 6316–6322.) and (Alexander, J. et al, J. Med. Chem. 1991, 34, 78–81).
A carboxylic acid (1 equivalent) is suspended in dry acetonitrile (2 ml per 0.1 mmol). Diisopropyl amine (3.0 equivalents) is added followed by bromomethyl acetate (1.5 equivalents). The mixture is stirred under nitrogen overnight at room temperature. Acetonitrile is removed under reduced pressure to yield an oil which is diluted in ethyl acetate and washed with water (3×). The organic layer is dried over anhydrous magnesium sulfate. Filtration followed by solvent removal under reduced pressure affords a crude oil. The product is purified by column chromatography on silica gel, using an appropriate solvent system.
Definitions
As used herein, the term “attached” or “—”(e.g. —C(O)—R13, which indicates the carbonyl attachment point to the scaffold) signifies a stable covalent bond, certain preferred points of attachment points being apparent to those skilled in the art.
The terms “halogen” or “halo” include fluorine, chlorine, bromine, and iodine.
The term “alkyl” includes C1–C6 straight chain saturated, methylene and C2–C6 unsaturated aliphatic hydrocarbon groups, C1–C6 branched saturated and C2–C6 unsaturated aliphatic hydrocarbon groups, C3–C6 cyclic saturated and C5–C6 unsaturated aliphatic hydrocarbon groups, and C1–C6 straight chain or branched saturated and C2–C6 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C3–C6 cyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, and the like. The alkyl group as defined above is optionally substituted wherein the substitutents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, hydroxy, oxo, COOR3, CONR9R10, C1–C6alkyl, C1–C6alkyloxy, aryloxy, arylC1–C6alkyloxy, thio, C1–C6alkylthio, arylthio, arylC1–C6alkylthio, NR9R10, C1–C6alkylamino, arylamino, arylC1–C6alkylamino, di(arylC1–C6alkyl)amino, C1–C6alkylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy, arylcarboxy, arylC1–C6alkylcarboxy, C1–C6alkylcarbonylamino, —C1–C6alkylaminoCOR14, arylC1–C6alkylcarbonylamino, tetrahydrofuranyl, morpholinyl, piperazinyl, —CONR9R10, —C1–C6-alkylCONR9R10, or a saturated or partial saturated cyclic 5, 6 or 7 membered amine, imide or lactam; wherein R14 is hydroxy, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkyloxy, aryloxy, arylC1–C6alkyloxy and R3 is defined as above or NR9R10, wherein R9, R10 are defined as above.
The term “saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system” represents but are not limit to aziridinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, indolyl, isoindolyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinoxalinyl, indolinyl, indazolyl, benzimidazolyl, benzotriazolyl, purinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, iminodibenzyl, iminostilbenyl.
The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an “alkyl” group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term “alkyloxyalkyl” represents an “alkyloxy” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “alkyloxyalkyloxy” represents an “alkyloxyalkyl” group attached through an oxygen atom as defined above having the indicated number of carbon atoms.
The term “aryloxy” (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
The term “arylalkyloxy” (e.g. phenethyloxy, naphthylmethyloxy and the like) represents an “arylalkyl” group as defined below attached through an oxygen bridge.
The term “arylalkyloxyalkyl” represents an “arylalkyloxy” group as defined above attached through an “alkyl” group defined above having the indicated number of carbon atoms.
The term “arylthio” (e.g. phenylthio, naphthylthio and the like) represents an “aryl” group as defined below attached through an sulfur bridge.
The term “alkyloxycarbonyl” (e.g. methylformiat, ethylformiat and the like) represents an “alkyloxy” group as defined above attached through a carbonyl group.
The term “aryloxycarbonyl” (e.g. phenylformiat, 2-thiazolylformiat and the like) represents an “aryloxy” group as defined above attached through a carbonyl group.
The term “arylalkyloxycarbonyl” (e.g. benzylformiat, phenyletylformiat and the like) represents an “arylalkyloxy” group as defined above attached through a carbonyl group.
The term “alkyloxycarbonylalkyl” represents an “alkyloxycarbonyl” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
The term “arylalkyloxycarbonylalkyl” represents an “arylalkyloxycarbonyl” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
The term “alkylthio” (e.g. methylthio, ethylthio, propylthio, cyclohexenylthio and the like) represents an “alkyl” group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term “arylalkylthio” (e.g. phenylmethylthio, phenylethylthio, and the like) represents an “arylalkyl” group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
The term “alkylthioalkyl” represents an “alkylthio” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “arylalkylthioalkyl” represents an “arylalkylthio” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “alkylamino” (e.g. methylamino, diethylamino, butylamino, N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, pyrrolidinyl, piperidinyl and the like) represents one or two “alkyl” groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two alkyl groups may be taken together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, NR9R10, C1–C6alkylaminoC1–C6alkyl substituent wherein the alkyl and aryl groups are optionally substituted as defined in the definition section and R9 and R10 are defined as above. The term “arylalkylamino” (e.g. benzylamino, diphenylethylamino and the like) represents one or two “arylalkyl” groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two “arylalkyl” groups may be taken together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, NR9R10, C1–C6alkylaminoC1–C6alkyl substituent wherein the alkyl and aryl groups are optionally substituted as defined in the definition section and R9 and R10 are defined as above.
The term “alkylaminoalkyl” represents an “alkylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “arylalkylaminoalkyl” represents an “arylalkylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “arylalkyl” (e.g. benzyl, phenylethyl) represents an “aryl” group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl) represents an “alkyl” group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term “arylcarbonyl” (benzoyl) represents an “aryl” group as defined above attached through a carbonyl group.
The term “arylalkylcarbonyl” (e.g. phenylcyclopropylcarbonyl, phenylethylcarbonyl and the like) represents an “arylalkyl” group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term “alkylcarbonylalkyl” represents an “alkylcarbonyl” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
The term “arylalkylcarbonylalkyl” represents an “arylalkylcarbonyl” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an “alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term “arylcarboxyalkyl” (e.g. phenylcarboxymethyl) represents an “arylcarbonyl” group defined above wherein the carbonyl is in turn attached through an oxygen bridge to an alkyl chain having the indicated number of carbon atoms.
The term “arylalkylcarboxy” (e.g. benzylcarboxy, phenylcyclopropylcarboxy and the like) represents an “arylalkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term “alkylcarboxyalkyl” represents an “alkylcarboxy” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
The term “arylalkylcarboxyalkyl” represents an “arylalkylcarboxy” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
The term “alkylcarbonylamino” (e.g. hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl) represents an “alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term “arylalkylcarbonylamino” (e.g. benzylcarbonylamino and the like) represents an “arylalkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term “alkylcarbonylaminoalkyl” represents an “alkylcarbonylamino” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term “arylalkylcarbonylaminoalkyl” represents an “arylalkylcarbonylamino” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term “alkylcarbonylaminoalkylcarbonyl” represents an alkylcarbonylaminoalkyl group attached through a carbonyl group. The nitrogen atom may be further substituted with an “alkyl” or “aryl” group.
The term “aryl” represents a substituted or unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalo-methyl, C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, COOR3, CONR9R10, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxy, arylC1–C6alkyloxy, arylC1–C6alkyloxyC1–C6alkyl, thio, C1–C6alkylthio, C1–C6alkylthioC1–C6alkyl, arylthio, arylC1–C6alkylthio, arylC1–C6alkylthioC1–C6alkyl, NR9R10, C1–C6-alkylamino, C1–C6alkylaminoC1–C6alkyl, arylamino, arylC1–C6alkylamino, arylC1–C6alkyl-aminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarbonylC1–C6alkyl, arylC1–C6alkylcarbonyl, arylC1–C6alkyl-carbonylC1–C6alkyl, C1–C6alkylcarboxy, C1–C6alkylcarboxy-C1–C6alkyl, arylC1–C6alkylcarboxy, arylC1–C6alkylcarboxyC1–C6alkyl, carboxyC1–C6alkyl-oxy, C1–C6alkylcarbonylamino, C1–C6alkylcarbonylaminoC1–C6alkyl, -carbonylNR7C1–C6alkylCOR14, arylC1–C6alkylcarbonylamino, arylC1–C6alkylcarbonylaminoC1–C6alkyl, —CONR9R10, or —C1–C6alkylCONR9R10; wherein R3, R9, R10, and R14 are defined as above and the alkyl and aryl groups contained therein are optionally substituted as defined above. The definition of aryl includes but is not limited to phenyl, biphenyl, indenyl, fluorenyl, naphthyl(1-naphthyl, 2-naphthyl), pyrrolyl(2-pyrrolyl), pyrazolyl(3-pyrazolyl), imidazolyl(1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl(2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl(3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl(2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl(2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl(2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl(2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl), 5-tetrazolyl, pyrimidinyl(2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl(3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo-[b]furanyl), 6-(2,3-dihydro-benzo-[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]-thiophenyl(2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]-thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]-thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]-thiophenyl)), 4,5,6,7-tetrahydro-benzo[b]thiophenyl (2-(4,5,6,7-tetrahydro-benzo-[b]thiophenyl), 3-(4,5,6,7-tetrahydro-benzo-[b]thiophenyl), 4-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 5-(4,5,6,7-tetrahydro-benzo-[b]thiophenyl), 6-(4,5,6,7-tetrahydro-benzo-[b]thiophenyl), 7-(4,5,6,7-tetrahydro-benzo[b]thiophenyl)), 4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl(4-(4,5,6,7-tetrahydro-thieno[2,3-c pyridyl), 5-4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 6-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 7-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl)), indolyl(1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl(1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), 1,3-dihydro-isoindolyl(1-(1,3-dihydro-isoindolyl), 2-(1,3-dihydro-isoindolyl), 3-(1,3-dihydro-isoindolyl), 4-(1,3-dihydro-isoindolyl), 5-(1,3-dihydro-isoindolyl), 6-(1,3-dihydro-isoindolyl), 7-(1,3-dihydro-isoindolyl)), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl(1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl(1-benzothiazolyl, 2-benzo-thiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz-[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz-[b,f]azepine-4-yl, 5H-dibenz[b,f]-azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz-[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), piperidinyl(2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl(1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), phenylpyridyl(2-phenyl-pyridyl, 3-phenyl-pyridyl, 4-phenylpyridyl), phenylpyrimidinyl(2-phenylpyrimidinyl, 4-phenylpyrimidinyl, 5-phenylpyrimidinyl, 6-phenylpyrimidinyl), phenylpyrazinyl, phenylpyridazinyl(3-phenylpyridazinyl, 4-phenylpyridazinyl, 5-phenylpyridazinyl).
The term “arylcarbonyl” (e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl) represents an “aryl” group as defined above attached through a carbonyl group.
The term “arylalkylcarbonyl” (e.g. (2,3-dimethoxyphenyl)propylcarbonyl, (2-chloronaphthyl)pentenylcarbonyl, imidazolylcyclopentylcarbonyl) represents an “arylalkyl” group as defined above wherein the “alkyl” group is in turn attached through a carbonyl.
The term “aryloxyalkyl” represents an “aryloxy” group as defined above attached through an “alkyl” group defined above having the indicated number of carbon atoms.
The term “arylaminocarbonylaminoalkyl” represents an “arylaminocarbonylamino” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
The term “R8R9Nalkyl” is as defined under “substituted alkyl” or “optionally substituted alkyl”.
The term “arylaminoalkyl” represents an “arylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term “arylcarbonylaminoalkyl” represents an “arylcarbonylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
As used herein, the term “vicinity” applied with respect to the active site of a PTPase means the space occupied by a half sphere—with its apex pointing towards aspartic acid 48—having its center in the side chain nitrogen atom of the guanidinium group of residue 221 (arginine), which points away from the phosphate binding loop (residue Arg221 to Cys215). The radius of the half sphere is 27 Å.
As used herein, the term “structurally similar” means any PTPase that contains an aspartic acid in residue position 48 (PTP1B numbering—as defined in Chernoff et al, 1989, supra) and is more than 50% identical and preferably more than 65% identical and most preferably more than 80% identical to PTP1B (Chernoff et al., supra) and/or TC-PTP (Cool et al., Proc. Natl. Acad. Sci. U.S.A. 86: 5257–5261 (1989)) at the primary amino acid sequence level in the catalytic domain as defined below. Percent indentity can be determined using standard algorithms e.g. BLAST, BLASTP MEGALIGN, etc using default parameters.
As used herein, the term “catalytic domain” means the primary amino acid sequence of a PTPase that corresponds to the primary amino acid sequence between Asn 40 and Gln 262 (both residues included) in PTP1B (Chernoff et al., supra).
As used herein, the term “centroid” means the position for the stated atoms calculated by averaging the x coordinates of the atoms to obtain the x coordinate of the centroid, averaging the y coordinates of the atoms to obtain the y coordinate of the centroid, and averaging the z coordinates of the atoms to obtain the z coordinate of the centroid.
As used herein, the term “phosphate isostere” means a chemical group, which binds to one or more of the side chains or the main chain of the residues in the so-called P-loop or PTP signature motif of PTPases (i.e. Cys215-Xxx216-Xxx217-Xxx218-Xxx219-Xxx220-Arg221 (SEQ ID NO: 1), where Cys215 and Arg221 are absolutely conserved, whereas Xxx stands for less conserved residues). In PTP1B the P-loop residues are: Cys215-Ser216-Ala217-Gly218-Ile219-Gly220-Arg221 (SEQ ID NO: 2). As a non limiting example the following groups are phosphate isosteres: —CH2PO(OH)2, —CHFPO(OH)2, —CF2PO(OH)2, —NHCOCOOH, —OCH(COOH)2, —OCF(COOH)2, —OCH2COOH, —CONHCH2COOH, —CONHCHFCOOH and —CONHCF2COOH.
As used herein, the term “carboxylic acid isostere” means a compound resembling a carboxy group in its electronic and steric configuration and in its biological action (effecting inhibition of the class of structurally similar PTPases) but having a different chemical structure. As a non limiting example, the following residues and heterocycles are carboxylic acid isosteres: —CONH2, —SONH2, —SO2NH2,




As used herein the term “interact” or “interaction” when used in the context of a moiety or group of an inhibitor interacting with the active site or vicinity thereof of a PTPase, means the formation of noncovalent bonds, such as hydrogen bonds, salt bridges, hydrophobic interactions van der Waals forces, cation π interactions, or π, π interactions, aromatic—aromatic interactions, (Copeland, Enzymes—a practical introduction to structure, mechanism, and data analysis, VCH Publishers, Inc., New York (1996)) or by forming covalent bonds. Preferably, interactions between inhibitors of the invention and PTPs occur through non-covalent bonds.
As used herein, the term “hydrophobic” means a nonpolar chemical group (e.g. phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclohexyl, tert-butyl, isopropyl as nonlimiting examples) when present in the aqueous phase, in the vicinity of an enzyme, its hydrocarbon framework disturbs the degree of randomness of the water molecules, which forces the water molecules to associate by hydrogen bonding to form quasi-crystalline clusters or “ice-bergs”. This localized increase in the ordered structure of water will result in a loss of entropy, accompanied by an increase in the free energy of the system. Thus, a driving force operates to reject the hydrocarbon region of the drug/inhibitor from the aqueous phase so that binding to one or more similar hydrocarbon chain(s) within the enzyme molecule is facilitated.
As used herein, the term “hydrogen bond” means an association between an electronegative atom, e.g. fluorine, oxygen, nitrogen, or sulfur, and a hydrogen atom attached to another such electronegative atom.
As used herein, the term “salt bridge” means any electrostatic bond between positively and negatively charged groups.
The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
Pharmaceutically acceptable salts of the compounds of formula 1, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as —COOH, 5-tetrazolyl or —P(O)(OH)2, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethane sulfonate, picrate and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, can be used as the dosage form.
Also, in the case of the —COOH or —P(O)(OH)2 being present, pharmaceutically acceptable esters can be employed, e.g., methyl, tert-butyl, acetoxymethyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
As used herein, “treatment” shall include therapeutic or preventative management, treatment, cure, or palliation of a disease state or a measurable delay in its onset or recurrence or measurable reduction in its severity.
The term “therapeutically effective amount” shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other other biological or clinical investigator. Also included in the present invention is a process for isolation of PTPases via affinity purification procedures based on the use of immobilized compounds of the invention. Isolation can be effected using procedures otherwise well-known to those skilled in the art. Such methods, may be used to identify novel PTPases or other molecules with phosphotyrosine recognition units and to elucidate the function of both novel and previously identified PTPases. As a non-limiting example, compounds of the invention may be immobilized by coupling to a solid-phase support, such as as exemplified in examples 119 and 120. See also Example 121. A tissue sample or a sample from a cell line prepared as a lysate by methods well-known to those skilled in the art may be passed over said solid-phase coupled with a compound of the invention. After appropriate washing procedures designed to remove material that binds nonspecifically to said solid-phase, using standard procedures well known to those skilled in the art, mostly PTPases or other molecules with phosphotyrosine recognition units will be bound to the compounds of the invention coupled to the solid phase. Said PTPases or other molecules with phosphotyrosine recognition units may in turn be released by procedures well-known in the art and further subjected to amino acid sequence analysis according to standard procedures well-known to those skilled in the art. By back-translation of said amino acid sequence into a nucleotide sequence of the corresponding cDNA can be deduced using the appropriate genetic code. Said nucleotide sequence can be used to design and produce an equivalent oligonucleotide, which in turn can be used to identify partial or full-length cDNA clones from appropriate cDNA libraries encoding a protein or glycoprotein corresponding to or similar to the isolated PTPase or molecule with pTyr recognition units. Said oligonucleotide or isolated cDNA clone(s) can similarly be used to isolate genomic clones corresponding to said cDNA clones. Said partial or full-length cDNA can be inserted into appropriate vectors and expressed and purified proteins with procedures well known to those skilled in the art. Said purified proteins, in particular PTPases, may be used to further analyze the inhibitory capacity and selectivity of compounds of the invention as described.
The invention is further directed to compounds of the invention coupled to a suitable solid-phase matrix such as a Wang-resin or a Rink-resin, e.g., for further synthesis, combinational synthesis, or as a support for affinity purification.
The invention is further directed to a method for isolating a protein or a glycoprotein with affinity for a compound according to the invention from a biological sample, comprising:

    
    
        contacting a compound of the invention immobilized by coupling to a suitable solid-phase matrix with said biological sample in order for said immobilized compound to form a complex by binding said protein or glycoprotein,
        removing unbound material from said biological sample and isolating said complex, and
        extracting said protein or glycoprotein from said complex.
    
    


The invention is further directed to a method for isolating a protein-tyrosine phosphatase with affinity for a compound according to the invention from a biological sample, comprising

    
    
        contacting a compound of the invention immobilized by coupling to a suitable solid-phase matrix with said biological sample in order for said immobilized compound to form a complex by binding said protein-tyrosine phosphatase
        removing unbound material from said biological sample and isolating said complex
        extracting said protein-tyrosine phosphatase.
    
    


The following compounds are encompassed by the invention:

    5-(4-Chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(2,4-Dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4,5,6,7-Tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(1,3-Dioxo-1,3-dihydro-benzo[f]isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    Oxalic acid (3-carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)ester methyl ester;
    Oxalic acid (3-carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)ester;
    7-Hydroxymethyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(((Benzo[1,3]dioxole-5-carbonyl)-amino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(3-Imidazol-1-yl-2,5-dioxo-pyrrolidin-1-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    2-(Oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 7-ethyl ester;
    7-Benzylcarbamoyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-(4-Chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(3-(2,4-Dimethoxy-phenyl)-ureidomethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    2-((3-Carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)-carbamoyl)-nicotinic acid;
    5-(4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(5,7-Dioxo-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindol-6-ylmethyl2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(2,4-Dioxo-5-pyridin-2-ylmethylene-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(2,4-Dioxo-5-pyridin-2-ylmethyl-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(5-(4-Methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(5-(4-Acetylamino-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(5-(3,5-Dimethoxy-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(5-(1H-Imidazol-4(5)-ylmethylene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-((2-(4-Methanesulfonyl-phenyl)-acetylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(1,3-Dioxo-4,7-epoxido-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-((2-Amino-3-phenyl-propionylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(((2R)-2-Amino-3-phenyl-propionylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-((2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-((2-Acetylamino-3-methyl-butyrylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-c]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5-Nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(5-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-Nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    2-(Oxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran 3-carboxylic acid;
    2-(Oxalyl-amino)-7-(3-oxo-3H-benzo[d]isoxazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-ethyl ester;
    5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    (L)-5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(((Benzo[1,3]dioxole-5-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(4-(4-Chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl methyl)-2-(oxalyl-amino)-4,7-dihyro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-(3-(2,4-Dimethoxy-phenyl)-ureidomethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-((2-(4-Methanesulfonyl-phenyl)acetylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    7-((2-Acetylamino-3-(4-hydroxy-phenyl)propionylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
    5-(S)-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-5-(S)-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(7-Benzyloxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    6-(4-Methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)-acetylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(R)-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(S)-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(S)-(Oxalyl-amino)-5-((4-phenoxy-benzylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(S)-((4-Acetylamino-benzylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(S)-((Acetyl-(4-phenoxy-benzyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(S)-((Acetyl-benzyl-amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(S)-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(6-Methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid;
    7-(R)-Carbamoyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-5-(S)-phenylcarbamoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    2-(Oxalyl-amino)-7-(R)-phenylcarbamoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    5-(R),7-(R)-Bis-benzyloxymethyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
    6-Benzyl-2-(oxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof


PHARMACOLOGICAL METHODS
The compounds are evaluated for biological activity with a truncated form of PTP1B (corresponding to the first 321 amino acids), which was expressed in E. coli and purified to apparent homogeneity using published procedures well-known to those skilled in the art. The enzyme reactions are carried out using standard conditions essentially as described by Burke et al. (Biochemistry 35; 15989–15996 (1996)) incorporated by reference. The assay conditions are as follows. Appropriate concentrations of the compounds of the invention (e.g., 0.1 to 100 μM) are added to the reaction mixtures containing different concentrations of the substrate, p-nitrophenyl phosphate (range: 0.16 to 10 mM—final assay concentration). The buffer used was 50 mM HEPES pH 7.0, 100 mM sodium chloride, 0.1% (w/v) bovine serum albumin, 5 mM glutathione, and 1 mM EDTA. The reaction was started by addition of the enzyme and carried out in microtiter plates at 25° C. for 60 minutes. The reactions are stopped by addition of NaOH. The enzyme activity was determined by measurement of the absorbance at 405 nm with appropriate corrections for absorbance at 405 nm of the compounds and p-nitrophenyl phosphate. The data are analyzed using nonlinear regression fit to classical Michaelis Menten enzyme kinetic models. Inhibition is expressed as Ki values in μM. The results of representative experiments are shown in Table 6.







TABLE 6







Inhibition of classical PTPases by compounds of the invention









Ki (μM) at pH 7













PTP1B
TC-PTP
PTP α
PTP β
PTP ε



residue
residue
residue
residue
residue



48
48
48
48
48


Example No.
Asp
Asp
Asn
Asn
Asn















48
0.25

900
47
380


49
0.085


8.6


50
0.07

1000
8


52
1.2

>400
107
>500









The Synthesis of the Compounds

In accordance with one aspect of the invention, compounds of the invention are prepared as illustrated in the following reaction schemes wherein n, m, X, Y, R1, R2, R3, R4, R5 and R6 are defined as above:




a) NCCH2COOR3, sulphur, morpholine or triethylamine, ethanol; b) R3OCOCOimidazole, tetrahydrofuran; c) 25% trifluoroacetic acid/dichloromethane.

Method B

The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, water, and physiologic saline.
Similarly, the carrier or diluent may include any material that impacts controlled release of taste-masking properties, known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
Generally, the compounds of this invention are dispensed in unit dosage form comprising 10–200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 1–500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
A typical tablet that may be prepared by conventional tabletting techniques contains













Core:




















Active compound (as free compound
100
mg



or salt thereof)



Colloidal silicon dioxide (Areosil ®)
1.5
mg



Cellulose, microcryst. (Avicel ®)
70
mg



Modified cellulose gum (Ac-Di-Sol ®)
7.5
mg



Magnesium stearate























Coating:





















HPMC
approx.
9
mg



*Mywacett ® 9-40 T
approx.
0.9
mg







*Acylated monoglyceride used as plasticiser for film coating.






The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
EXAMPLES
The process for preparing compounds of Formula 1 and preparations containing them is further illustrated in the following examples, which, however, are not to be construed as limiting.
Hereinafter, TLC is thin layer chromatography, CDCl3 is deuterio chloroform, CD3OD is tetradeuterio methanol and DMSO-d6 is hexadeuterio dimethylsulfoxide. The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts (δH) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in ° C. and is not corrected. Column chromatography was carried out using the technique described by W. C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5 μm C18 4×250 mm column eluted with various mixtures of water and acetonitrile, flow=1 ml/min, as described in the experimental section.
Wang-resin is polystyrene with a 4-hydroxymethylphenol ether linker. Compounds used as starting material are either known compounds or compounds which can readily be prepared by methods known per se.
Example 1




5-(4-Chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a mixture of benzyloxyacetaldehyde (8.3 g, 0.06 mol) in benzene (80 mL) was added 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (10.6 g, 0.06 mol). The reaction mixture was stirred under nitrogen for 15 min., cooled to 0° C. and a solution of 0.5 M zinc chloride (55 ml, 0.03 mol) was added dropwise. The reaction mixture was allowed to warm to room temperature over 16 h and evaporated in vacuo. The resultant oil was diluted with ethyl acetate (100 ml), washed with 1N hydrochloric acid (3×50 ml), saturated sodium bicarbonate (3×50 ml), brine (3×50 ml), dried (MgSO4) and evaporated in vacuo. The resulting oil was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:2) as eluant. Pure fractions were collected affording after evaporation in vacuo 7.1 g (60%) of benzyloxy-methyl-2,3-dihydro-pyran-4-one as an oil.
1H NMR (400 MHz, CDCl3) δ 7.39–7.31 (m, 6H), 5.42 (dd, J=6, 1 Hz, <1H), 4.61 (d, J=3 Hz, 1H), 4.57 (m, 1H), 3.70 (m, 2H), 2.74 (dd, J=17 Hz, 14 Hz, 1H), 2.41 (ddd, J=17 Hz, 2 Hz, 1 Hz, 1H).
The above 2,3-dihydro-pyran-4-one (7.1 g, 0.032 mol) and 10% palladium on carbon (0.4 g) in ethyl acetate (50 ml) were placed in a Parr bomb shaker and hydrogenated at 30 psi. The reaction mixture was shaken for 2 h, at which time TLC analysis (methanol/dichloromethane 1:9) indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite and the volatiles evaporated in vacuo. The residue was subjected to flash column chromatography using ethyl acetate as eluant. Pure fractions were collected affording after evaporation in vacuo 3.0 g (75%) of 2-hydroxymethyl-tetrahydro-pyran-4-one as an oil.
1H NMR (400 MHz, CDCl3) δ4.36–4.29 (m, 1H), 3.77–3.66 (m, 3H), 3.61–3.54 (m, 1H), 2.65–2.43 (m, 2H), 2.34–2.27 (m, 2H), 2.04 (bs, 1H, CH2OH).
The above tetrahydro-pyran-4-one (1.90 g, 0.015 mol), tert-butyl cyanoacetate (2.7 g, 0.019 mol), sulfur (0.51 g, 0.016 mol) and morpholine (2.55 ml, 0.03 mol) were dissolved in absolute ethanol (20 ml), and heated to 50° C. for 16 h. The reaction mixture was cooled, filtered and the filtrate evaporated in vacuo. The resultant oil was dissolved in ethyl acetate (50 ml), washed with water (2×50 ml), brine (2×50 m) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was subjected to flash column chromatography using ethyl acetate/hexanes (1:1) as eluant. Pure fractions were collected affording after evaporation in vacuo 3.7 g (90%) of 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (400 MHz, CDCl3) δ 4.64 (s, 2H), 3.80–3.67 (m, 3H), 2.77–2.72 (m, 1H), 2.57–2.53 (m, 1H), 1.54 (s, 9H).
The above carboxylic acid tert-butyl ester (1.0 g, 3.5 mmol), 4-chloro-1,3-dioxo-1,3-dihydro-isoindol (0.67 g, 3.7 mmol) and triphenylphosphine (1.01 g, 3.9 mmol) were dissolved in dry tetrahydrofuran (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Diisopropyl azodicarboxylate (DIAD) (0.62 ml, 3.9 mmol) was added dropwise at 0° C. and the solution allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in ethyl acetate (50 ml). The organic phase was washed with brine (3×50 ml), dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash column chromatography (300 ml silicagel) using a mixture of ethyl acetate/hexanes (1:3) as eluant. Semi pure fractions were collected affording after evaporation in vacuo 0.7 g which was trituated with diethyl ether. The solid was filtered off and washed with diethyl ether and dried in vacuo affording 0.13 g (27%) of 2-amino-5-(4-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid. The filtrate was evaporated in vacuo. The residue (0.48 g) was subjected to flash column chromatography (300 ml silicagel) using a mixture of ethyl acetate/hexanes (1:3) as eluant. Pure fractions were collected affording after evaporation in vacuo an additional 0.36 g (23%) of 2-amino-5-(4-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
To the above 4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert butyl ester (0.36 g, 0.8 mmol) dissolved in tetrahydrofuran (20 ml) was added a mixture of imidazol-1-yl-oxo-acetic acid tert butyl ester (0.31 g, 1.6 mmol) in tetrahydrofuran (3.4 ml) under nitrogen. The reaction mixture was allowed to stir at room temperature for 18 hours. An additional portion of imidazol-1-yl-oxo-acetic acid tert butyl ester (0.3 g, 1.6 mmol) in tetrahydrofuran (2 ml) was added. The reaction mixture was allowed to stir at room temperature for an additional 60 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with brine (3×50 ml) dried (Na2SO4), filtered and the organic phase evaporated in vacuo. The residue (0.5 g) was purified by column chromatography (300 ml silicagel) using a mixture of ethyl acetate/heptane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.36 g (80%) of 2-(tert-butoxyoxalyl-amino)-5-(4-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
The above di-tert-butyl ester (0.3 g, 0.52 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.5 ml) was added. The reaction was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the residue trituated with a mixture of diethyl ether and heptane (1:1) (5 ml). The precipitate was filtered off, washed with heptane and diethyl ether, dried in vacuo at 50° C. for 18 h which afforded 200 mg (69%) of the title compound as a solid.
M.p.: >250° C.
Calculated for C19H13N2ClO8S; C, 49.09%; H, 2.82%; N, 6.03%. Found: C, 48.79%; H, 2.79%; N, 5.89%.
Example 2




5-(4,5,6,7-Tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
In a 4 ml scintillating vial, a solution of tetrachloro phthalimide (148 mg, 0.52 mmol) in N,N-dimethylformamide (2.0 ml) was heated to 100° C. for 10 minutes and treated with potassium hydride (55 mg, 0.48 mmol, 35% w/w dispersion in mineral oil). The resulting mixture was stirred until gas generation ended, 2-(tert-butoxyoxalyl-amino)-5-(4-nitro-benzenesulfonyl-oxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (151 mg, 0.25 mmol) and 18-crown-6 ether (31 mg, 0.12 mmol) were added. The solution was flushed with nitrogen gas before being stirred at 80° C. for 25 h. The volatiles were evaporated in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (5:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 39 mg (23%) of 2-(tert-butoxyoxalyl-amino)-5-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 12.50 (s, 1H), 4.80 (d, J=16, 1H), 4.67 (d, J=14, 1H), 4.14–3.99 (m, 2H), 3.84 (d, J=9, 1H), 2.99 (d, J=17, 1H), 2.70 (dd, J=17, 5, 1H), 1.60 (s, 9H), 1.56 (s, 9H).
HPLC (254.4 nm) Rt=5.80 min, 95%.
In a 25 ml round bottom flask, 2-(tert-butoxyoxalyl-amino)-5-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (39 mg, 0.06 mmol) was dissolved in 20% trifluoroaceetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring for 24 h. A precipitate was filtered off and washed with diethyl ether, affording after drying 29 mg (90%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H), 4.76 (d, J=16, 1H), 4.59 (d, J=14, 1H), 4.0–3.6 (m partially obscured by water, 3H), 3.1 (d partially obscured by water, J=17, 1H), 2.61 (dd partially obscured by DMSO, J=20, 11, 1H).
HPLC (254.4 nm) Rt=4.15 min, 75%.
Example 3




5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo. The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in methanol (8 ml) and 1N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 h., after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 h., at which time a precipitate had formed. The mixture was acidified with 6N hydrochloric acid until pH=1, causing the solution to become homogeneous. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51%) of 4-methoxy-phthalic acid as a solid.
1H NMR (300 MHz, CD3OD) δ 7.83 (d; J=8, 1H), 7.10–7.06 (m, 2H), 3.87 (s, 3H).
LC-MS: Rt=1.45 min, [M+H]+=197.1
A solution of 4-methoxy-phthalic acid (0.10 g, 0.51 mmol), 1-hydroxy-benzotriazole (0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.22 g, 1.1 mmol), and triethylamine (0.35 ml, 2.5 mmol) was prepared in distilled acetonitrile (4 ml) under nitrogen. 2-Amino-5-aminomethyl-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol) was added in small portions and the reaction was stirred at ambient temperature for 18 h., and then concentrated in vacuo. The crude mixture was diluted in ethyl acetate (30 ml) and washed with 1% hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 10% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 54 mg (31%) of 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8, 1H), 7.32 (s, 1H), 7.14 (d, J=8, 1H), 4.62–4.48 (m, 2H), 4.00–3.72 (m, 3H), 3.91 (s, 3H), 2.86 (d, J=17, 1H), 2.55 (dd, J=17, 10, 1H), 1.49 (s, 9H).
To a solution of the above 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (54 mg, 0.12 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.25 g, 0.36 mmol) and triethylamine (50 μl, 0.36 mmol). The reaction was stirred for 4 h., concentrated in vacuo and the residue reconstituted in ethyl acetate (20 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic phase was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 5% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 56 mg (81%) of 2-(tert-butoxyoxalyl-amino)-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 12.48 (s, 1H), 7.75 (d, J=8, 1H), 7.32 (d, J=2, 1H), 7.15 (dd, J=8, 2, 1H), 4.78 (d, J=15, 1H), 4.65 (d, J=15, 1H), 4.03–3.75 (m, 3H), 3.91 (s, 3H), 2.95 (d, J=17, 1H), 2.66 (dd, J=17, 9, 1H), 1.58 (s, 9H), 1.54 (s, 9H).
APCI-MS: [M+H]+=574
The above 2-(tert-butoxyoxalyl-amino)-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (55 mg, 0.096 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (4 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 17 mg (40%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H), 7.81 (d, J=8, 1H), 7.40 (d, J=2, 1H), 7.31 (dd, J=8, 2, 1H), 4.75 (d, J=15, 1H), 4.56 (d, J=15, 1H), 3.92 (s, 3H), 3.91–3.69 (m, 3H), 2.98 (d, J=17, 1H), 2.57 (dd, J=17, 9, 1H).
APCI-MS: [M−H]−=459
HPLC (254.4 nm): Rt=3.36 min, 98%
Example 4




5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was prepared in a similar way as described in Example 1.
To a solution of the above benzylether (0.7 g, 1.08 mmol) in ethyl acetate (50 ml) was added 10% palladium on carbon (0.2 g). The mixture was hydrogenated at 1 atm. for 5 h, filtered and the volatiles evaporated in vacuo. The residue (0.6 g) was purified by column chromatography (500 ml silicagel) using a mixture of ethyl acetate/heptane (1:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.4 g (67%) of 2-(tert-butoxyoxalyl-amino)-5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
TLC: Rf=0.2 (ethyl acetate/heptane 1:1)
The above di-tert-butyl ester (0.4 g, 0.72 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane (25 ml). The reaction was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the residue trituated with diethyl ether (5 ml). The precipitate was filtered off, washed with heptane and diethyl ether, dried in vacuo at 50° C. for 18 h which afforded 230 mg (72%) of the title compound as a solid.
M.p.: >250° C.;
Calculated for C19H14N2O9S, 0.5×H2O; C, 50.11%; H, 3.32%; N, 6.15%. Found: C, 50.06%; H, 3.17%; N, 5.98%.
Example 5




5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.7 g, 1.08 mmol) (prepared in a similar way as described in Example 1) was dissolved in 25% trifluoroacetic acid in dichloromethane (25 ml). The reaction was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the residue trituated with diethyl ether (25 ml). The precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. for 3 hours which afforded 400 mg (69%) of the title compound as a solid.
M.p.: 194–196° C.;
Calculated for C26H20N2O9S, 1×H2O, 0.6×CF3COOH; C, 52.44%; H, 3.66%; N, 4.50%. Found: C, 52.33%; H, 3.65%; N, 4.62%.
Example 6




5-(4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
Prepared in a similar way as described in Example 1.
M.p.: >250° C.;
Calculated for C19H13FN2O8S, 1×H2O; C, 48.93%; H, 3.24%; N, 6.01%. Found: C, 48.90%; H, 3.15%; N, 5.86%.
Example 7




5-(1,3-Dioxo-1,3-dihydro-benzo[f]isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid,
In a 4 ml scintillating vial, a solution of benzo[f]isoindole-1,3-dione (145 mg, 0.74 mmol) in N,N-dimethylformamide (2.0 ml) was treated with potassium hydride (55 mg, 0.48 mmol, 35% w/w dispersion in mineral oil). The resulting mixture was stirred until gas generation ended and the resulting precipitate was filtered off and washed with dichloromethane which afforded 121 mg (69%) of benzo[f]isoindole-1,3-dione potassium salt as a solid.
1H NMR (300 MHz, D2O) δ 8.00–7.87 (m, 4H), 7.62 (s, 2H).
In a 4 ml scintillating vial, the above potassium salt (121 mg, 0.5 mmol) in N,N-dimethylformamide (1.5 ml) was treated with 18-crown-6 ether (34 mg, 0.13 mmol) and 2-(tert-butoxyoxalyl-amino)-5-(4-nitro-benzene-sulfonyloxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (148 mg, 0.25 mmol). The solution was flushed with nitrogen gas before being stirred at 80° C. for 7 h. The volatiles were evaporated in vacuo and the residue purified by silica gel chromatography using a mixture of ethyl acetate/dichloromethane (1:49) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 85 mg (57%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-benzo[f]isoindole-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 12.52 (s, 1H), 8.37 (s, 2H), 8.08 (m, 2H), 7.72 (m, 2H), 4.84–4.65 (m, 2H), 4.16–3.90 (m, 3H), 3.02 (d, J=17, 1H), 2.73 (dd, J=17, 10, 1H), 1.61 (s, 9H), 1.58 (s, 9H).
In a 25 ml round bottom flask the above 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-benzo[f]isoindole-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (85 mg, 0.14 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring for 24 h. The precipitate was filtered off and washed with diethyl ether, affording after drying 62 mg (90%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.02 (s, 2) 4.81–4.59 (m, 2H), 3.97–3.81 (m partially obscured by water, 3H), 3.08 (d, J=18, 1H), 2.74–2.53 (m partially obscured by DMSO, 1H).
Example 8




5-(5-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of N-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-acetamide (51 mg, 0.25 mmol) in N,N-dimethylformamide (1.5 ml) under nitrogen at room temperature was added potassium hydride (35 wt. % dispension in mineral oil, 29 mg, 0.25 mmol). The solution was stirred at room temperature for 3 hours. A solid precipitated during this period. 2-(tert-Butoxyoxalyl-amino)-5-(4-nitro-benzene-sulfonyloxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol) was added to the suspension and the solution was stirred at 80° C. for 12 h. The solvent was evaporated in vacuo, the resulting residue purified by silica gel chromatography using a gradient of ethyl acetate/hexane (10–25%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 50 mg (50%) of 5-(5-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (CDCl3): δ 12.53 (s, 1H), 8.03 (d, 1H, J=1.5 Hz), 7.91 (dd, 1H, J=7.8, 1.8 Hz) 7.83 (d, 1H, J=8.1 Hz), 7.45 (s, 1H), 4.80 (d, 1H, J=16 Hz), 4.66 (d, 1H, J=16 Hz), 4.03 (m, 2H), 3.83 (q, 1H, J=15 Hz), 2.98 (d, 1H, J=9 Hz), 2.64–2.78 (m, 1H), 2.27 (s, 3H), 1.62 (s, 9H), 1.57 (s, 9H).
To a mixture of trifluoroacetic acid/dichloromethane (2 ml, 1:1) at room temperature was added the above 5-(5-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (40 mg, 0.067 mmol). The solution was stirred for 5 h. at which time the solvent was removed in vacuo. The residue was washed with dichloromethane, filtered off, and dried in vacuo which afforded 23 mg (70%) of the title compound as a solid.
1H NMR (DMSO-d6): δ 12.32 (s, 1H), 10.58 (s, 1H), 8.21 (s, 1H) 7.84 (s, 2H), 4.76 (d, 1H, J=15 Hz), 4.58 (d, 1H, J=15 Hz), 3.80–4.00 (m, 3H), 3.00 (d, 1H, J=17 Hz), 2.58–2.73 (m, 1H), 2.13 (s, 3H).
MS: 488 (M+1).
Example 9




5-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described for Example 8.
1H NMR (DMSO-d6): δ 12.32 (s, 1H), 9.76 (s, 1H), 8.45 (d, 1H, J=8.4 Hz) 7.79 (t, 1H, J=8.4 Hz), 7.58 (d, 1H, J=8.4 Hz), 4.77 (d, 1H, J=15 Hz), 4.58 (d, 1H, J=15 Hz), 3.68–3.94 (m, 3H), 3.02 (d, 1H, J=16 Hz), 2.55–2.78 (m, 1H), 2.20 (s, 3H).
MS: 488 (M+1).
Example 10




5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
In a 4-ml scintillating vial, a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (148 mg, 0.5 mmol) in tetrahydrofuran (1.0 ml) was treated with a solution of pyrazine phthtalic acid anhydride (85 mg, 0.56 mmol) in tetrahydrofuran (1.0 ml) and N,N-dimethylformamide (0.5 ml). The reaction mixture was allowed to stir at room temperature for 1 h. Diisopropylethylamine (220 μl, 0.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.6 mmol) were then added. The reaction mixture was shaken vigorously for 10 seconds before being stirred at room temperature for 14 h. The volatiles were evaporated in vacuo and the residue purified by silica gel chromatography using a mixture of dichloromethane/ethyl acetate (3:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 25 mg (12%) of the 2-amino-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 8.97 (s, 2H), 4.62–4.49 (m, 2H), 4.21–4.04 (m, 2H), 3.94 (dd, J=14, 4, 1H), 2.91 (d, J=17, 1H), 2.63 (dd, J=17, 10, 1H), 1.68 (s, 9H).
In a 4 ml scintillating vial a solution of the above 2-amino-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (25 mg, 0.06 mmol) in tetrahydrofuran (3 ml) was treated with midazol-1-yl-oxo-acetic acid tert-butyl ester (0.36 mmol). After stirring for 3 hours at room temperature the reaction solution was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (3:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 31 mg (95%) of 2-(tert-butoxyoxalyl-amino)-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 12.49 (s, 1H), 8.96 (s, 2H), 4.80–4.61 (m, 2H), 4.21–4.04 (m, 2H), 3.96 (dd, J=14, 4, 1H), 3.03 (d, J=16, 1H), 2.70 (dd, J=17, 10, 1H), 1.60 (s, 9H), 1.59 (s, 9H).
In a 25 ml round bottom flask the above 2-(tert-butoxyoxalyl-amino)-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester, (31 mg, 0.06 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring for 24 h. A precipitate was filtered off and washed with diethyl ether, affording after drying 22 mg (90%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.02 (s, 2), 4.81–4.59 (m, 2H), 3.97–3.81 (m partially obscured by water, 3H), 3.08 (d, J=18, 1H), 2.74–2.53 (m partially obscured by DMSO, 1H).
HPLC (254.4 nm) Rt=2.97 min, 89%.
MS (APCI) [M−H] 432.4
Example 11




7-(5,7-dihydro-5-pyrrolo[3,4-b]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
A solution of furo[3,4-b]pyridine-5,7-dione (86.1 mg, 0.58 mmol) and of 2-(tert-butoxyoxalyl-amino)-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (194 mg, 0.47 mmol) in acetonitrile (2.0 ml) was stirred for 10 min. at room temperature. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89.2 mg, 0.564 mmol) and triethylamine (198 μl, 1.41 mmol) were added and the mixture was stirred at room temperature for 20 h. The volatiles were removed in vacuo and the crude product dissolved in dichloromethane (60 ml) and washed with water (3×30 ml). The organic layer was dried (MgSO4), filtered and the solvent removal in vacuo. The residue (338 mg) was purified by column chromatography on silica gel utilizing a mixture of hexane/ethyl acetate (90/10 to 50/50) as gradient which afforded after evaporation of the solvent in vacuo 85 mg (33%) of 2-(tert-butoxyoxalyl-amino)-7-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-4,7-dihyd-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl-ester as an oil.
1H NMR (300 MHz, CDCl3), δ 9.00 (d, J=48, 1H), 8.21 (d, J=7.5, 1H), 7.64 (dd, J=4.8, J=6.8, 1H), 5.12 (d, J=7.2, 1H), 4.24–4.1 (m, 2H), 3.97–3.91 (m, 1H), 3.75 (m, 1H), 2.90 (m, 1H), 1.29 (s, 9H), 1.27 (s, 9H).
MS: 544 (M+1).
The above 2-(tert-butoxyoxalyl-amino)-7-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-4,7-dihyd-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (47.4 mg, 0.087 mmol) was stirred in 50% trifluoroacetic acid in dichloromethane (2 ml) at room temperature for 5 h. The solvent was removed in vacuo and the residue was washed with diethyl ether (4×3.0 ml) and dried which afforded 26.5 mg (70%) of the title compound as a solid.
1H NMR (400 MHz, CD3OD): δ 8.96 (d, J=5, 1H), 8.30 (d, J=7.6, 1H), 7.79 (dd, J=5.2, J=5.2, 1H), 5.10 (d, J=6.4, 1H), 4.16 (m, 2H), 3.96 (dd, J=3.2, J=3.6, 1H), 3.78 (m, 1H), 2.95 (m, 2H).
MS: 432 (M+1).
Example 12




5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
Pyrrolo[3,4-b]pyridine-5,7-dione (74.2 mg, 0.5 mmol) was stirred with sodium hydride (60% dispersion in mineral oil, 20.04 mg, 0.5 mmol) in N,N-dimethylformamide (4.0 ml) at room temperature under inert atmosphere. 2-(tert-Butoxyoxalyl-amino)-5-(4-nitro-benzene-sulfonyloxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (198 mg, 0.33 mmol) was added to the sodium salt formed and the reaction was stirred at 80° C. for 20 h. The solvent was removed in vacuo and the crude product was purified by preparative TLC (hexane:ethyl acetate 50:50) which afforded 58 mg (21%) of 2-(tert-butoxyoxalyl-amino)-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3): δ 9.00 (d, J=5, 1H), 8.20 (d, J=7.5, 1H), 7.65 (dd, J=5, J=5, 1H), 4.80 (d, J=14.7, 1H), 4.66 (d, J=14.7, 1H), 4.10 (m, 2H), 3.91 (d, J=13.2, 1H), 3.02 (d, J=16.5, 1H), 2.70 (m, 1H), 1.61 (s, 9H), 1.58 (s, 9H).
MS: 544 (M+1).
The above 2-(tert-butoxyoxalyl-amino)-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (46.4 mg, 0.09 mmol) was stirred in 20% trifluoroacetic acid in dichloromethane (3.0 ml) at room temperature for 2 h. The volatiles were removed in vacuo and the residue was washed with diethyl ether (5×3 ml) affording 37 mg (99%) of the title compound as a solid.
1H NMR (300 MHz, CDCl3): δ 8.96 (d, J=5.4, 1H), 8.20 (d, J=7.7, 1H), 7.64 (m, 1H), 4.77 (d, J=14.7, 1H), 4.61 (d, J=14.7, 1H), 4.07 (m, 2H), 3.86 (d, J=10.5, 1H), 3.12 (d, J=17.4, 1H), 2.77–2.68 (m, 2H).
MS: 432 (M+1).
Example 13




5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-c]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of pyrrolo[3,4-c]pyridine-1,3-dione (74 mg, 0.50 mmol) in N,N-dimethylformamide (1 ml) under nitrogen at room temperature was added potassium hydride (35 wt. % dispersion in mineral oil, 57 mg, 0.50 mmol). The solution was stirred at room temperature for 3 hours. A solid precipitated during this period. 18-Crown-6 (33 mg, 0.13 mmol) and 2-(tert-butoxyoxalyl-amino)-5-(4-nitro-benzene-sulfonyloxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (150 mg, 0.25 mmol) were then added. The solution was stirred at 80° C. for 12 h and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (10–25%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 93 mg (68%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (CDCl3): δ 12.49 (s, 1H), 9.20 (s, 1H), 9.11 (d, 2H, J=4.8 Hz) 7.80 (d, 2H, J=4.8 Hz), 4.80 (d, 1H, J=16 Hz), 4.66 (d, 1H, J=16 Hz), 4.00–4.18 (m, 2H), 3.70–3.95 (m, 1H), 3.01 (d, 1H, J=17 Hz), 2.64–2.78 (m, 1H), 1.60 (s, 9H), 1.59 (s, 9H).
To a mixture of trifluoroacetic acid/dichloromethane (1 ml, 1:1) at room temperature was added the above 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (29 mg, 0.053 mmol). The solution was stirred for 5 h. and the solvent evaporated in vacuo. The residue was washed with dichloromethane afford after drying in vacuo 22 mg (96%) of the title compound as a solid.
1H NMR (DMSO-d6): δ 12.32 (s, 1H), 9.15 (s, 1H), 9.11 (d, 2H, J=4.8 Hz) 7.92 (d, 2H, J=4.8 Hz), 4.76 (d, 1H, J=15 Hz), 4.58 (d, 1H, J=16 Hz), 3.75–4.00 (m, 4H), 3.04 (d, 1H, J=17 Hz).
MS: 432 (M+1).
Example 14




5-(5-Nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
In a 4-ml scintillating vial, a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (58 mg, 0.2 mmol) in tetrahydrofuran (2.0 ml) was treated with 4-nitrophthalic acid (63 mg, 0.3 mmol), diisopropylethylamine (190 μl, 1.1 mmol), and 1,3-diisopropylcarbodiimide (120 μl, 0.77 mmol). The reaction mixture was shaken vigorously for 10 seconds before being stirred at 50° C. for 43 hours and at room temperature for 20 h. The solution was diluted with ethyl acetate (25 ml), washed with 0.5N aqueous hydrochloric acid (25 ml), saturated aqueous sodium bicarbonate (25 ml), and brine (25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. Crude 2-amino-5-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was obtained as a solid and used immediately in the next step.
In a 4 ml scintillating vial a solution of the above crude 2-amino-5-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester in dichloromethane (3 ml) was treated with midazol-1-yl-oxo-acetic acid tert-butyl ester (147 mg, 0.75 mmol). After stirring for 2 h. at room temperature the reaction mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (3:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo which afforded 30 mg (26%) of 2-(tert-butoxyoxalyl-amino)-5-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 12.47 (s, 1H), 8.71 (s, 1H), 8.64 (d, J=8, 1H), 8.08 (d, J=9, 1H), 4.79 (d, J=14, 1H), 4.65 (d, J=14, 1H), 4.21–3.97 (m, 2H), 3.89 (d, J=12, 1H), 3.01 (d, J=16, 1H), 2.83–2.61 (m, 1H), 1.63 (ds, 18H).
In a 25 ml round bottom flask, the above 2-(tert-butoxyoxalyl-amino)-5-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) was dissolved in a mixture of 20% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring of 24 h. A precipitate was filtered off and washed with diethyl ether, affording after drying 22 mg (90%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.63 (d, J=8, 1H), 8.15 (d, J=8, 1H), 4.76 (d, J=16, 1H), 4.57 (d, J=16, 1H), 4.42–3.74 (m partially obscured by water, 3H), 3.04 (d partially obscured by water, J=16, 1H), 2.61 (m partially obscured by DMSO, 1H).
HPLC (254.4 nm) Rt=3.40 min, 86%.
MS (APCI+) [M+H] 407.6
Example 15




5-(5-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 4-hydroxyphthalic acid (0.45 g, 2.47 mmol) in anhydrous N,N-dimethylformamide (5 ml) under nitrogen was added chloromethyl methyl ether (1.13 ml, 14.8 mmol) and diisopropylethylamine (2.6 ml, 14.8 mmol). The reaction was stirred at ambient temperature for 18 h. and then concentrated in vacuo. The crude material was partitioned between ethyl acetate (50 ml) and water (15 ml). The layers were separated, the organic layer washed with water (3×10 ml), brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in ethanol (5 ml) and sodium hydroxide (0.12 g, 7.4 mmol) dissolved in water (1 ml) was added to the reaction. The solution was stirred at ambient temperature for 48 h. and then concentrated in vacuo affording 4-methoxymethoxy-phthalic acid di-sodium salt which was used without purification.
1H NMR (300 MHz, CD3OD) δ 7.59 (d, J=8, 1H), 7.06 (d, J=3,1H), 6.89 (dd, J=8, 3, 1H), 5.18 (s, 2H), 3.42 (s, 3H).
A solution of 4-methoxymethoxy-phthalic acid di-sodium salt (0.19 g, 0.70 mmol), 1-hydroxybenzotriazole (0.2 g, 3.6 equiv.), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.28 g, 3.6 equiv.), and triethylamine (0.33 ml, 6 equiv.) was prepared in distilled acetonitrile (5 ml) under nitrogen. The mixture was stirred for 5 minutes before 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (115 mg, 0.40 mmol) was added in small portions. The reaction was stirred at ambient temperature for 18 h., then concentrated in vacuo. The crude mixture was diluted with ethyl acetate (30 ml) and washed with 1% hydrochloric acid (5 ml) saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (5 to 10% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 44 mg (23%) of 2-amino-5-(5-methoxy-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8, 1H), 7.48 (d, J=2, 1H), 7.27 (dd, J=8, 2, 1H), 5.26 (s, 2H), 4.60–4.46 (m, 2H), 3.99–3.71 (m, 3H), 3.47 (s, 3H), 2.85 (d, J=17, 1H), 2.55 (dd, J=17, 9, 1 H), 1.48 (s, 9H).
To a solution of the above 2-amino-5-(5-methoxy-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl, ester (44 mg, 0.095 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (56 mg, 0.29 mmol) and triethylamine (26 μl, 0.19 mmol). The reaction was stirred for 4 h., concentrated in vacuo and reconstituted in ethyl acetate (20 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 5% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 35 mg (63%) of 2-(tert-butoxyoxalyl-amino)-5-(5-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 12.50 (s, 1H), 7.75 (d, J=8, 1H), 7.49 (d, J=2, 1H), 7.28 (dd, J=8, 2, 1H), 5.26 (s, 2H), 4.77 (d, J=15, 1H), 4.64 (d, J=15, 1H), 4.03–3.74 (m, 3H), 3.47 (s, 3H), 2.95 (d, J=17, 1H), 2.65 (dd, J=17, 9, 1H), 1.58 (s, 9H), 1.54 (s, 9H).
APCI-MS: [M+H]+=603.7
The above 2-(tert-butoxyoxalyl-amino)-5-(5-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (35 mg, 0.058 mmol) was dissolved in a mixture of 50% trifluoroacetic acid/dichloromethane (2.5 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 20 mg (77%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.97 (s, 1H), 7.72 (d, J=8, 1H), 7.18 (s, 1H), 7.10 (d, J=8, 1H), 4.74 (d, J=15, 1H), 4.58 (d, J=15, 1H), 3.96–3.62 (m, 3H), 2.99 (d, J=17, 1H), 2.60–2.50 (m, 1H, partially obscured by DMSO).
APCI-MS: [M−H]−=445.4
HPLC (254.4 nm): Rt=2.92 min, 95%
Example 16




5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 h. and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo, diluted in ethyl acetate (20 ml) and the organic phase washed with 1N hydrochloric acid (5 ml) and brine (3×5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 h. and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47%) of 4-methoxy-isobenzofuran-1,3-dione as a solid.
1H NMR (300 MHz, DMSO-d6) δ 7.95 (t, J=8, 1H), 7.61 (d, J=8, 1H), 7.58 (d, J=8, 1H), 3.99 (s, 3H).
APCI-MS: [M+H]+=179.1
A solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (122 mg, 0.43 mmol, prepared as described in Example 17) and 4-methoxy-isobenzofuran-1,3-dione (92 mg, 0.52 mmol) was prepared in distilled tetrahydrofuran (4 ml) under nitrogen. 1-hydroxybenzotriazole (87 mg, 0.65 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.65 mmol), and triethylamine (0.29 ml, 2.15 mmol) were added. The reaction was stirred at ambient temperature for 18 h., then concentrated in vacuo. The crude mixture was diluted with ethyl acetate (25 ml) and washed with 1N hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 0.18 g (94%) of 2-amino-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 7.66 (t, J=7, 1H), 7.43 (d, J=7, 1H), 7.19 (d, J=7, 1H), 4.59–4.46 (m, 2H), 4.06–3.72 (m, 3H), 4.00 (s, 3H), 2.87–2.81 (m, 1H), 2.60–2.51 (m, 1H), 1.48 (s, 9H).
To a solution of the above 2-amino-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.18 g, 0.42 mmol) in distilled dichloromethane (5 ml) under nitrogen was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.25 g, 1.26 mmol) and triethylamine (0.23 ml, 1.68 mmol). The reaction was stirred for 12 h., concentrated in vacuo and reconstituted in ethyl acetate (25 ml). The organic layer was washed with 1N hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (0 to 10% gradient). Pure fractions were collected and the solvent evaporated in vacuo to give 195 mg (81%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 12.48 (s, 1H), 7.65 (t, J=7, 1H), 7.43 (d, J=7, 1H), 7.19 (d, J=7, 1H), 4.77 (d, J=15, 1H), 4.63 (d, J=15, 1H), 4.04–3.75 (m, 3H), 4.00 (s, 3H), 2.94 (d, J=17, 1H), 2.65 (dd, J=17, 10, 1H), 1.58 (s, 9H), 1.53 (s, 9H).
LC-MS: Rt=4.17 min, [M+H]+=573.2
The above 2-(tert-butoxyoxalyl-amino)-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.15 g, 0.26 mmol) was dissolved in a mixture of 50% trifluoroacetic acid/dichloromethane (5 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 100 mg (83%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.79 (t, J=8, 1H), 7.48 (d, J=8, 1H), 7.42 (d, J=8, 1H), 4.74 (d, J=15, 1H), 4.56 (d, J=15, 1H), 3.95 (s, 3H), 3.91–3.79 (m, 2H), 3.69–3.63 (m, 1H), 2.98 (d, J=17, 1H), 2.57 (dd, J=17, 10, 1H).
LC-MS: Rt=1.26 min, [M+H]+=461.0
HPLC (254.4 nm): Rt=3.10 min, 100%
Example 17




5-(4-Nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
In a 50-ml round-bottom flask, a suspension of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2.00 g, 4.8 mmol) in absolute ethanol (20 ml) was flushed with nitrogen and sealed with a rubber septum. Hydrazine (0.5 ml, 15.9 mmol) was added, followed by an additional portion of absolute ethanol (20 ml) at room temperature. The reaction mixture was heated to 80° C. for 3.5 h., then allowed to stir at room temperature for 14 h. The precipitate was filtered off and washed with absolute ethanol. The filtrate was concentrated in vacuo leaving an oil, which was dissolved in dichloromethane (30 ml) and refiltered. The solvent was evaporated in vacuo affording 1.2 g (86%) of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) d 5.92 (s, 2H), 4.64 (s, 2H), 3.68–3.60 (m, 1H), 2.98–2.74 (m, 3H), 2.56–2.44 (m, 1H), 1.54 (s, 9H).
MS (APCI+) [M+H] 285.3
In a 4-ml scintillating vial, a solution of the above 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (63 mg, 0.2 mmol) in tetrahydrofuran (2.0 ml) was treated with 3-nitro-phthalic acid (66 mg, 0.3 mmol), diisopropylethylamine (190 μl, 1.1 mmol), and 1,3-diisopropyl-carbodiimide (120 μl, 0.77 mmol). The reaction mixture was shaken vigorously for 10 seconds before being stirred at 50° C. for 43 hours and at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 0.5N aqueous hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), and brine (25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo affording crude 2-amino-5-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) 4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
In a 4 ml scintillating vial a solution of the above crude 2-amino-5 (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester in dichloromethane (3 ml) was treated with midazol-1-yl-oxo-acetic acid tert-butyl ester (147 mg, 0.75 mmol). After stirring for 2 h. at room temperature the reaction solution was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (3:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 30 mg (26%) of 2-(tert-butoxyoxalyl-amino)-5-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 8.17 (d, J=5, 1H), 8.11 (d, J=6, 1H), 7.94 (t, J=8, 1H), 4.80 (d, J=14, 1H), 4.67 (d, J=15, 1H), 4.16–3.97 (m, 3H), 3.88 (d, J=10, 1H), 3.01 (d, J=16, 1H), 2.70 (dd, J=16, 10, 1H), 1.62 (s, 9H), 1.59 (s, 9H).
In a 25 ml round bottom flask, the above 2-(tert-butoxyoxalyl-amino)-5-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) was dissolved in a mixture of 20% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After standing for 24 h. a precipitate was filtered off and washed with diethyl ether, affording after drying 22 mg (90%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.32 (d, J=9, 1H), 8.20 (d, J=9, 1H), 8.07 (t, J=9, 1H), 4.77 (d, J=14, 1H), 4.59 (d, J=16, 1H), 4.00–3.65 (m partially obscured by water, 3H), 3.04 (d partially obscured by water, J=16, 1H), 2.63 (dd partially obscured by DMSO, J=17, 13, 1H).
HPLC (254.4 nm) Rt=3.33 min, 100%.
MS (APCI+) [M+H] 391.6
Example 18




5-(4-(4-Chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
Under a nitrogen atmosphere, 4-(4-chloro-phenylsulfanyl)-6-methyl-pyrrolo[3,4-c]-1,3-dione (914 mg, 3.0 mmol), tributylphosphine (1.66 ml, 4.5 mmol) and 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (855 mg, 3.0 mmol) were successively dissolved in dry benzene (90 ml). Solid azodicarboxylic dipiperidine (1.13 g, 4.5 mmol) was added under stirring at 0° C. to the solution. After stirring for 10 min, the reaction mixture was brought to room temperature and the stirring continued for 4 h. The mixture was cooled on ice, and additional portions of tributylphosphine (1.66 ml, 4.5 mmol) and azodicarboxylic dipiperidine (1.13 g, 4.5 mmol) were added. After stirring for 10 min, the reaction mixture was brought to room temperature and the stirring continued for 18 h. Heptane (30 ml) was added to the reaction and the precipitate filtered off (discard). After evaporation of the solvent the product was purified by flash chromatography to give 1.3 g (76%) of 2-amino-5-(4-(4-chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Mp: 118–119° C.;
1H NMR (CDCl3) δ 1.55 (s, 9H), 2.50 (s, 3H), 2.50–2.65 (m, 1H), 2.85–2.95 (m, 1H), 3.75–3.85 (m, 1H), 3.95–4.05, (m, 2H), 4.50–4.15 (m, 2H), 5.95 (bs, 2H), 7.30 (s, 1H), 7.40 (d, 2H), 7.55 (d, 2H).
To an ice cooled solution of 2-amino-5-(4-(4-chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (572 mg, 1 mmol) and dry triethylamine (2 ml) in dry tetrahydrofuran (10 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (588 mg, 3 mmol). After 10 min, the reaction mixture was brought to room temperature and the stirring continued for 18 h. The mixture was concentrated in vacuo and submitted to flash chromatography using a mixture of toluene/ethyl acetate (30:1) as eluant. Pure fraction were collected and the solvent evaporated in vacuo to give 360 mg (51%) of 2-(tert-butoxyoxalyl-amino)-5-(4-(4-chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
M.p.: 134–136° C.;
1H NMR (CDCl3) δ 1.60 (s, 9H), 1.63 (s, 9H), 2.50 (s, 3H), 2.65–2.75 (m, 1H), 2.95–3.05 (m, 1H), 3.75–3.90 (m, 1H), 4.00–4.10, (m, 2H), 4.60–4.85 (m, 2H), 7.30 (s, 1H), 7.40 (d, 2H), 7.55 (d, 2H), 12.50 (s, 1H).
To 2-(tert-butoxyoxalyl-amino)-5-(4-(4-chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (324 g, 0.46 mmol) was added a mixture of trifluoroacetic acid (2.5 ml) and dichloromethane (7.5 ml). The mixture was stirred for 5 h, and added petroleum ether/ethyl acetate. The precipitate was isolated off and re-suspended in ethyl acetate. The title compound 136 mg (50%) was isolated by filtration.
Mp: 239–240° C.;
Calculated for C25H18ClN3O8S2, 0.75×H2O; C, 49.92%; H, 3.27%; N, 6.99%. Found: C, 49.83%; H, 3.16%; N, 6.85%.
1H NMR (CDCl3) δ 2.48 (s, 3H), 2.65–2.75 (m, 1H), 2.95–3.05 (m, 1H), 3.50–4.00 (m, 3H), 4.50–4.90 (m, 2H), 7.50–7.68 (m, 5H), 12.30 (s, 1H).
Example 19




5-(3-Imidazol-1-yl-2,5-dioxo-pyrrolidin-1-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.53 g, 1.86 mmol, prepared as described in Example 17) in tetrahydrofuran (10 ml) was added, maleic acid (0.24 g, 2.05 mmol) and diisopropylcarbodiimide (0.58 ml, 3.72 mmol). The reaction mixture was heated to reflux for 3 hours and then allowed to cool to room temperature over an 18 hour period. The solvent was stripped off in vacuo and the residue diluted into ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (2×50 ml), 1% hydrochloric acid (2×20 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo affording an oil which was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (6:4) as eluant. Pure fractions (Rf=0.25) were collected and the solvent evaporated in vacuo to give 0.60 g (90%) of 2-amino-5-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 7.31 (d, J=5.7, 1H), 6.63 (d, J=5.4, 1H), 5.94 (bs, 2H), 4.67 (s, 2H), 3.93 (m, 1H), 3.82 (m, 2H), 2.89–2.83 (m, 1H), 2.69–2.60 (m, 1H), 1.54 (s, 9H).
MS: APCI (+): 365.2 (M+H);
To a solution of the above 2-amino-5-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (60 mg, 1.64 mmol) in tetrahydrofuran (2 ml) was added midazol-1-yl-oxo-acetic acid tert-butyl ester (50 mg, 2.46 mmol). The solution was stirred at room temperature for 48 h. The solvent was stripped off in vacuo and the resultant oil diluted in ethyl acetate (20 ml), washed with brine (3×25 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected preparative thin layer chromatography using a mixture of methanol/dichloromethane (1:9) as eluant which afforded 25 mg (28%) of 2-(tert-butoxyoxalyl-amino)-5-(3-imidazol-1-yl-2,5-dioxo-pyrrolidin-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a mixture of diastereoisomers.
1H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 6.94 (s, 1H), 5.92 (m, 1H), 5.22 (m, 1H), 4.68–4.53 (m, 2H), 4.00 (m, 3H), 3.71 (m, 1H), 3.47–3.38 (m, 1H), 3.03–2.87 (m, 1H), 2.61 (m, 1H), 1.60 (s, 9H), 1.54 (s, 9H).
MS: APCI (+): 561.2 (M+H).
To the above 2-(tert-butoxyoxalyl-amino)-5-(3-imidazol-1-yl-2,5-dioxo-pyrrolidin-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (25 mg, 0.05 mmol) was added a mixture of 20% trifluoroacetic acid in dichloromethane (2 ml). The reaction mixture was allowed to stir at room temperature for 2 h., at which time the mixture was concentrated in vacuo. The resultant solid was triturated with diethyl ether (2×) which afforded 13 mg (65%) of the title compound as a solid.
1H NMR (300 MHz, CD3OD) δ9.15 (s, 1H), 7.78 (s, 1H), 7.63 (m, 1H), 5.75 (m, 1H), 4.69 (m, 2H), 4.46 (m, 1H), 3.85 (m, 2H), 3.66 (m, 1H), 3.02 (m, 1H), 2.83 (m, 1H), 2.64 (m, 1H), 2.46 (m, 1H).
MS: ESI (−): 447.4 (M−H).
Example 20




Oxalic acid 3-carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester methyl
To a solution of 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (8.0 g, 28 mmol) in dry tetrahydrofuran (50 ml) was added midazol-1-yl-oxo-acetic acid tert-butyl ester (27.51 g, 0.14 mol) and triethylamine (3.93 ml, 0.14 mol). The reaction mixture was stirred at room temperature for 20 h. The volatiles were removed in vacuo and the crude product was dissolved in ethyl acetate (300 ml) and washed with a saturated solution of sodium bicarbonate (3×100 ml), dilute hydrochloric acid (3×100 ml), water (3×100 ml) and brine (100 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo affording a foam (16 g) which was purified on column chromatography on silica gel using a gradient of hexane/ethyl acetate (90:10 to 50:50 gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo which afforded 11 g (91%) of oxalic acid 2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3): δ 5.94 (s, 2H), 4.86 (d, J=14.7, 1H), 4.77 (d, J=14.4, 1H), 4.64 (m, 1H), 3.82–3.71 (m, 2H), 2.85 (d, J=16.8, 1H), 2.68 (d, J=10.5, 1H), 1.62 (s, 9H), 1.61 (s, 9H).
MS: 414 (M+1).
A solution of the above oxalic acid 2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester tert-butyl ester (8.3 g, 20.1 mmol) and potassium carbonate (1.7 g, 12.3 mmol) was stirred in methanol (80 ml) in presence of water (3 ml) at room temperature for 10 min., at which time TLC indicated reaction complete. Methanol was removed in vacuo and the crude product was dissolved in dichloromethane (300 ml) and washed with water (3×150 ml). The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified on flash chromatography on silica gel using a gradient of hexane/ethyl acetate (90:10 to 50:50 gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.65 g (9%) of oxalic acid 2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester methyl ester as a solid.
1H NMR (300 MHz, CDCl3): δ4.86 (d, J=15, 1H), 4.78 (d, J=15, 1H), 4.00 (s, 3H), 3.82–3.70 (m, 3H), 2.86 (d, J=17, 1H), 2.66 (dd, J=10.2, J=10.5, 1H), 1.62 (s, 9H).
MS: 316 (M−55).
To a solution of the above oxalic acid 2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester methyl ester (160 mg, 0.43 mmol) in dry tetrahydrofuran (3.0 ml) was added midazol-1-yl-oxo-acetic acid tert-butyl ester (420.4 mg, 2.15 mmol) and triethylamine (120 μl, 0.86 mmol). The resulting mixture was stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel using a gradient of hexane/ethyl acetate (95:5 to 80:20 gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 173 mg (81%) of oxalic acid 2-amino-3-tert-butoxycarbonyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester methyl ester as a solid.
1H NMR (300 MHz, CDCl3): δ 4.81 (dd, J=14.7, J=14.2, 2H), 4.40 (m, 2H), 4.00 (s, 3H), 2.96 (d, J=15.3, 1H), 2.69 (dd, J=10.8, J=10.8, 1H), 1.61 (s, 9H), 1.57 (s, 9H).
MS: 388.3 (M−11).
The above oxalic acid 2-amino-3-tert-butoxycarbonyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester methyl ester (93.8 mg, 0.19 mmol) was stirred in 20% trifluoroacetic acid in dichloromethane (2 ml) for 20 h. at room temperature. The solvent was removal in vacuo which afforded 73 mg (95%) of the title compound as a solid.
1H NMR (300 MHz, CD3OD): δ 4.76 (d, J=5.7, 2H), 4.18 (d, J=4.8, 2H), 3.97 (s, 3H), 2.99 (d, J=16.2, 1H), 2.65 (d, J=10.8, 1H).
MS: 386 (M−1).
Example 21




Oxalic acid (3-carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)ester
To a solution of a mixture of 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1:4 estimated based on 1H NMR) (200 mg, 0.70 mmol) and diisopropylethylamine (0.25 ml, 1.4 mmol) in dichloromethane (6.0 ml) cooled to 0° C. under nitrogen was added triethylchlorosilane (0.18 ml, 1.1 mmol). The solution was stirred at 0° C. for 5 min. and then stirred at room temperature for 15 min. The solution was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a 5% mixture of ethyl acetate/hexane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 42 mg (16%) of 2-amino-5-triethylsilanyloxymethy-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1) and 193 mg (69%) of 2-amino-7-triethylsilanyloxymethy-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2).
(1) 1H NMR (CDCl3): δ 4.58 (m, 1H), 4.18–4.07 (m, 1H), 3.84 (dd, 1H, J=9.6, 6.0 Hz); 3.80–3.70 (m, 1H), 3.60 (dd, 1H, J=9.6, 7.8 Hz), 2.92–2.70 (m, 2H), 1.58 (s, 9H), 0.98 (t, 9H, J=7.8 Hz), 0.64 (q, 6H, J=7.8 Hz);
(2) 1H NMR (CDCl3): δ 4.62 (s, 2H), 3.85–3.64 (m, 3H), 2.82 (dm, 1H, J=15 Hz), 2.49 (dd, 1H, J=15, 11 Hz), 1.58 (s, 9H), 0.98 (t, 9H, J=7.8 Hz), 0.64 (q, 6H, J=7.8 Hz).
To a solution of 2-amino-7-triethylsilanyloxymethy-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (6.0 g, 15 mmol) in dichloromethane (10 ml) cooled to 0° C. under the nitrogen was added a solution of imidazol-1-yl-oxo-acetic acid tert-butyl ester (4.5 g, 18 mmol) in dichloromethane. The solution was stirred at 0° C. for 10 min. The reaction was quenched with water (1.0 ml). The solution was washed with brine and dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a 10% mixture of ethyl acetate/hexane as eluant. Pure fractions of two compounds were collected and the solvent evaporated in vacuo affording 4.5 g (56%) of 2-(tert-butoxyoxalyl-amino)-7-triethylsilanyloxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (A) as a solid and 50 mg of oxalic acid 3-(tert-butoxycarbonyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (B) as a solid.
(A) 1H NMR (CDCl3): δ 12.53 (s, 1H), 4.85 (d, 1H, J=12 Hz), 4.65 (d, 1H, J=12 Hz), 3.90–3.60 (m, 3H), 2.94 (d, 1H, J=15 Hz), 2.63 (dd, 1H, J=15, 11 Hz), 1.63 (s, 9H), 1.61 (s, 9H), 0.98 (t, 9H, J=7.8 Hz), 0.64 (q, 6H, J=7.8 Hz).
(B) 1H NMR (CDCl3): δ 12.47 (s, 1H), 4.82 (q, 2H, J=14 Hz), 4.43 (m, 2H), 4.01 (m, 1H), 2.97 (d, 1H, J=14 Hz), 2.69 (dd, 1H, J=19, 9 Hz), 1.63 (s, 9H), 1.61 (s, 9H), 1.58 (s, 9H).
To a solution of the above 2-(tert-butoxyoxalyl-amino)-7-triethylsilanyloxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.5 g, 8.5 mmol) in tetrahydrofuran (10 ml) at room temperature was added 0.5 N hydrochloric acid (2.0 ml). The solution was stirred at room temperature for 0.5 h. Ethyl acetate (100 ml) was added and the resulting solution was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a 10% mixture of ethyl acetate/hexane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 3.0 g (84%) of 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (CDCl3): δ 12.53 (s, 1H), 4.86 (d, 1H, J=12 Hz), 4.60 (d, 1H, J=12 Hz), 3.85–3.65 (m, 3H), 2.85 (d, 1H, J=15 Hz), 2.65 (dd, 1H, J=15, 11 Hz), 1.63 (s, 9H), 1.61 (s, 9H).
To a solution of the above 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (3.0 g, 7.1 mmol) in dichloromethane (10 ml) at room temperature was added pyridine (2.5 ml, 28.5 mmol) and 4-nitro-benzenesulfonyl chloride (4.7 g, 21.4 mmol). The solution was heated to 50° C. and stirred for 4.5 h. The solution was cooled to room temperature and washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (0–100%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 3.6 g (84%) of 2-(tert-butoxyoxalyl-amino)-7-(4-nitro-benzenesulfonyloxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (CDCl3): δ 12.40 (s, 1H), 8.43 (d, 2H, J=9.0 Hz), 8.17 (d, 2H, J=9.0 Hz), 4.72 (d, 1H, J=14 Hz), 4.64 (d, 1H, J=14 Hz), 4.38–4.24 (m, 2H), 3.98–3.86 (m, 1H), 2.92 (d, 1H, J=17 Hz), 2.65 (dd, 1H, J=17, 12 Hz), 1.63 (s, 9H), 1.61 (s, 9H).
MS: 598 (M−1).
To a solution of 50% trifluoroacetic acid/dichloromethane (1 ml) at room temperature was added oxalic acid 3-(tert-butoxycarbonyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (50 mg, 0.092 mmol). The solution was stirred for 3 hours. The solvent was removed in vacuo. The residue was washed with dichloromethane affording after filtration 25 mg (73%) of the title compound as a solid.
1H NMR (DMSO-d6): δ12.32 (s, 1H), 4.82 (d, 1H, J=15 Hz), 4.68 (d, 1H, J=15 Hz), 4.37 (s, 1H), 3.92 (m, 1H), 2.93 (d, 1H, J=16 Hz), 2.60 (dd, 1H, J=30, 10 Hz).
MS: 372 (M−1).
Example 22




7-Hydroxymethyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a mixture of 2-hydroxymethyl-tetrahydro-pyran-4-one (35 g, 0.27 mol), tert-butyl cyanoacetate (58.68 ml g, 0.4 mol), and sulphur (9.47 g, 0.3 mol) in absolute ethanol (400 ml) was added morpholin (47 ml, 0.54 mol), and the resulting mixture was heated to 45° C. for 16 h. The reaction mixture was cooled, filtered and the filtrate evaporated in vacuo. The resultant oil was dissolved in ethyl acetate (600 ml), washed with water (3×200 ml), brine (200 m), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was crystallised from diethyl ether (100 ml) followed by addition of a mixture of diethyl ether and heptane (100 ml, 1:1). The precipitate was filtered off, washed with a mixture of diethyl ether and heptane (90 ml, 1:1) and dried in vacuo at 50° C. for 52 h affording 44.51 g of a mixture of 5 and 7 regioisomers according to NMR. The mixture of regioisomers (44.51 g) was suspended in diethyl ether (500 ml) and stirred at room temperature for 96 h. and at reflux temperature for 2 h. After cooling to room temperature the precipitate was filtered off and washed with a mixture of diethyl ether and heptane (100 ml, 1:1) which afforded after drying in vacuo at 50° C., 22.12 g (29%) of 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
All filtrates were pooled and evaporated in vacuo affording 55 g of a mixture of regioisomers. To 40.16 g (0.141 mol) of this regioisomer mixture dissolved in dichloromethane (450 ml) was added diisopropyl-ethylamine (49.5 ml, 0.28 mol) and the mixture was cooled to 0° C. Chlorothiethylsilane (38.2 ml, 0.23 mol) was added dropwise and the mixture was stirred for 10 minutes and for 15 minutes at room temperature. The reaction mixture was washed with saturated aqueous sodium carbonate (3×150 ml), brine (3×150 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue (70.4 g) was partitioned into two portions which were subjected to flash chromatography (2 l silicagel) using a mixture of ethyl acetate/hexane (1:20) as eluant. Pure fractions of 2-amino-5-triethylsilanyloxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-amino-7-triethylsilanylhydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester were collected. A fraction containing both isomers (18.84 g) was re-subjected to flash chromatography (2 l silicagel) using a mixture of ethyl acetate/hexane (1:20) as eluant. A total of 28.1 g (50%) of 2-amino-5-triethylsilanylhydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was obtained. A total of 18.2 g (32%) of 2-amino-7-triethylsilanylhydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was obtained.
To the above 2-amino-7-triethylsilanylhydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (18.2 g, 0.046 mol) dissolved in dichloromethane (200 ml) was added a mixture of imidazol-1-yl-oxo-acetic acid tert butyl ester (17.9 g, 0.091 mol) in dichloromethane (30 ml) under nitrogen. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and washed with 1 N hydrochloric acid (3×50 ml), brine (3×75 ml), dried (Na2SO4), filtered and the organic phase evaporated in vacuo affording in quantitative yield 2-(tert-butoxyoxalyl-amino)-7-triethylsilanyloxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester ester as a oil.
To a mixture of the above 7-triethylsilanyl ether (24.0 g, 0.046 mol) in tetrahydrofuran (100 ml) was added 1 N hydrochloric acid (18 ml) and the reaction mixture was stirred at room temperature for 1.5 h. Ethyl acetate (150 ml) was added and the reaction mixture was washed with saturated aqueous sodium carbonate (3×100 ml), brine (3×100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was tritituated with a mixture of diethyl ether and heptane (1:5) and the precipitate was filtered off, washed with heptane and dried in vacuo at 50. ° C. for 16 h affording 13.55 g (57%) of 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
The above 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (16 mg, 0.033 mmol) was dissolved in 50% trifluoroacetic acid in dichloromethane (1 ml). The reaction was stirred at room temperature for 3 hours. The volatiles were evaporated in vacuo and the residue washed with dichloromethane which afforded 7 mg (73%) of the title compound as a solid.
1H NMR (DMSO-d6): δ 12.32 (s, 1H), 4.62 (s, 1H), 4.12 (m, 1H), 3.62–3.78 (m, 2H), 3.40–3.52 (m, 1H), 2.83 (m, 2H).
MS: 300 (M−1).
Example 23




7-(2,4-Dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.13 g, 0.46 mmol) in tetrahydrofuran (3 ml) was added triphenylphosphine (0.13 g, 0.51 mmol), and 2,4-thiazolidinedione (60 mg, 0.51 mmol). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (99 μL, 0.51 mmol) was added via syringe. The resultant mixture was stirred for 18 hours, gradually warming to room temperature. The volatiles were evaporated in vacuo and the resulting oil was diluted in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of dichloromethane/methanol (9:1) as eluant. Pure fractions were collected (Rf=0.70) and the solvent evaporated in vacuo which afforded 89 mg (51%) of 2-amino-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 6.02 (s, 2H), 4.82 (dm, 1H), 4.13–4.02 (bm, 2H), 3.99 (s, 2H), 3.75–3.67 (m, 1H), 3.60 (dd, 1H, J=14, 3.3,), 2.81–2.74 (m, 2H), 1.54 (s, 9H).
MS: APCI (+): 385.6 (M+H).
To a solution of the above of 2-amino-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (89 mg) in tetrahydrofuran (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (79 mg, 0.312 mmol) and the mixture allowed to stir overnight at room temperature. The volatiles were evaporated in vacuo, the residue diluted with ethyl acetate and subjected to preparative chromatography using a mixture of dichloromethane/methanol (9:1) as eluant. Material eluting with Rf=0.72 was collected and the solvent evaporated in vacuo affording 40 mg (25%) of 2-(tert-butoxyoxalyl-amino)-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 12.53 (s, 1H), 5.03 (dm, 1H), 4.12–4.04 (m, 2H), 4.01 (s, 2H), 3.79–3.71 (m, 2H), 2.88 (m, 2H), 1.62 (s, 9H), 1.59 (s, 9H).
MS: APCI (+): 513.3 (M+H).
The above 2-(tert-butoxyoxalyl-amino)-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (40 mg) was dissolved in 50% trifluoroacetic acid in dichloromethane (1 ml) and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, the residue titurated with dichloromethane and methanol which afforded after drying in vacuo 18 mg (87%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6+CD3OD) δ 4.98 (dm, 1H), 4.16 (s, 2H), 4.14–4.02 (m, 2H), 3.78–3.72 (m, 2H), 2.91 (m, 2H).
APCI (−): 399 (M−H);
LC-MS: s, 99%.
Example 24




7-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a mixture of 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.5 g, 1.2 mmol), 2-hydroxy-isoindole-1,3-dione (0.21 g, 1.3 mmol) and triphenylphosphine (0.35 g, 1.33 mmol) in dry tetrahydrofuran (20 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (205 μl, 1.33 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in ethyl acetate (50 ml). The organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×30 ml), water (3×50 ml), dried (Na2SO4), filtered and evaporated in vacuo. The residue (1.02 g) was subjected to flash column chromatography (300 ml silicagel) using a mixture of ethyl acetate/hexane (1:2) as eluant. Pure fractions were collected affording after evaporation in vacuo 0.37 g (54%) of 2-(tert-butoxyoxalyl-amino)-7-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
The above di-tert-butyl ester (0.33 g, 0.59 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane (2 ml). The reaction was stirred at room temperature for 6.5 h. The volatiles were evaporated in vacuo and the residue trituated with a mixture of diethyl ether and heptane (5 ml, 1:1). The precipitate was filtered off, washed with heptane and diethyl ether, dried in vacuo at 50° C. for 18 h which afforded 200 mg (77%) of the title compound as a solid.
M.p.: 251.5–254° C.;
Calculated for C19H14N2O9S; C, 51.12%; H, 3.16%; N, 6.28%. Found: C, 51.46%; H, 3.71%; N, 5.87%.
Example 25




7-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.5 g, 3.03 mmol) in anhydrous N,N-dimethylformamide (6 ml) under nitrogen was added diisopropylethylamine (1.05 ml, 6.06 mmol). The solution was stirred with cooling in an ice bath and chloromethyl methyl ether (0.46 ml, 6.06 mmol) was added. The reaction was allowed to slowly warm to ambient temperature and then stirred for an additional 7 h. The mixture was concentrated in vacuo to a small volume and diluted with ethyl acetate (75 ml). The organic layer was washed with water (2×40 ml), brine (20 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 0.6 g (95%) of 4-methoxymethoxy-isobenzofuran-1,3-dione as a solid.
1H NMR (400 MHz, CDCl3) δ 7.81 (t, J=8, 1H), 7.62 (d, J=8, 1H), 7.59 (d, J=8, 1H), 5.43 (s, 2H), 3.55 (s, 3H).
A mixture of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.15 g, 0.53 mmol) and 4-methoxymethoxy-isobenzofuran-1,3-dione (135 mg, 0.64 mmol) was dissolved in distilled acetonitrile (7 ml) under nitrogen. The flask was cooled in an ice bath with stirring and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g, 0.64 mmol), and triethylamine (0.22 ml, 1.59 mmol) were added. The reaction was warmed to ambient temperature and stirred for 18 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (40 ml). The organic layer was washed with 1% hydrochloric acid (2×10 ml), saturated sodium bicarbonate (10 ml), and brine (10 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo which afforded 0.18 g of a crude 2-amino-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester which was used without further purification.
1H NMR (400 MHz, CDCl3) δ 7.65–7.58 (m, 2H), 7.51 (d, J=8, 1H), 6.00–5.86 (2s, 2H), 5.39 (s, 2H), 4.94–4.89 (m, 1H), 4.18–4.02 (m, 2H), 3.86–3.65 (m, 2H), 3.54 (s, 3H), 2.85–2.73 (m, 2H), 1.55 (s, 9H).
APCI-MS: [M+H]+=475.4
To a solution of crude 2-amino-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.18 g) in distilled dichloromethane (4 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.23 g, 1.2 mmol). The reaction was stirred for 3 hours., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (0 to 5% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 90 mg (28% in two steps) of 2-(tert-butoxyoxalyl-amino)-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (400 MHz, CDCl3) δ 12.54 (s, 1H), 7.64 (t, J=8, 1H), 7.51 (d, J=8, 1H), 7.46 (d, J=8, 1H), 5.40 (s, 2H), 5.11–5.07 (m, 1H), 4.16–4.08 (m, 2H), 3.84–3.72 (m, 2H), 3.55 (s, 3H), 2.95–2.81 (m, 2H), 1.62 (s, 9H), 1.59 (s, 9H).
APCI-MS: [M+H]+=603.8
The above 2-(tert-butoxyoxalyl-amino)-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (86 mg, 0.143 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (4 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 55 mg (86%) of the title compound as a solid.
1H NMR (400 MHz, d6-DMSO) δ 12.34 (s, 1H), 11.10 (s, 1H), 7.63 (t, J=8, 1H), 7.31 (d, J=8, 1H), 7.22 (d, J=8, 1H), 4.99–4.95 (m, 1H), 4.05–4.00 (m, 1H), 3.91–3.86 (m, 1H), 3.76–3.66 (m, 2H), 2.88–2.80 (m, 2H).
APCI-MS: [M+H]+=447.4
HPLC (254.4 nm): Rt=2.921 min, 100%
Example 26




7-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic-acid
The title compound was prepared in a similar way as described in Example 25.
M.p.: 234–236° C.;
Calculated for C20H16N2O9S, 0.25×H2O; C, 51.67%; H, 3.58%; N, 6.03%. Found: C, 51.95%; H, 3.92%; N, 6.06%.
Example 27




7-(5,7-Dioxo-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindol-6-ylmethyl2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 25.
M.p.: 239.5–242.5° C.;
Calculated for C20H14N2O10S, 0.1×H2O; C, 50.45%; H, 3.01%; N, 5.88%. Found: C, 51.06%; H, 3.43%; N, 5.93%.
Example 28




7-(((Benzo[1,3]dioxole-5-carbonyl)-amino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
Phthalimidoacetaldehyde diethyl acetal (100 g, 0.38 mol) and 1 N hydrochloric acid (600 ml) was mixture was stirred at reflux temperature for 5 min. or until a homogeneous solution is obtained. The reaction mixture was cooled and the precipitate was filtered off and dried in vacuo at 50° C. for 16 h which afforded 63.3 g (88%) of phthalimidoacetaldehyde as a solid.
1H NMR (300 MHz, CDCl3) δ 4.58 (s, 2H), 7.76–7.78 (m, 2H), 7.90–7.92 (m, 2H), 9.67 (s, 1H).
To a mixture of phthalimidoacetaldehyde (64 g, 0.34 mol) and trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (81.5 g, 0.38 mol) in benzene (600 ml) stirred for 15 min. under nitrogen was added dropwise a 45% solution of zinc chloride diethyl ether complex in dichloromethane (55.5 ml, 0.17 mol) at 0° C. The reaction was allowed warm up to room temperature overnight. To the reaction mixture was added water (500 ml) and the resulting mixture was extracted with ethyl acetate (200 ml). The organic extract was washed successively with 1.0 N hydrochloric acid (2×200 ml) and brine (200 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated in vacuo which afforded a slowly crystallising oil (98 g). To the solid was added a mixture of ethyl acetate and diethyl ether (400 ml, 1:1) and the resulting precipitate was filtered off, washed with a small portion of diethyl ether and dried at 50° C. for 1 h affording 59.8 g (69% of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid. The filtrate was evaporated in vacuo and the residue purified by column chromatography on silica gel (1 L) using a mixture of ethyl acetate and heptane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo to almost dryness, the solid was filtered off and dried in vacuo at 50° C. for 16 h affording an additional 15 g (17%) of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
1H NMR (300 MHz, CDCl3) δ 2.61 (d, 2H), 3.85 (dd, 1H), 4.18 (dd, 1H), 4.76 (m, 1H), 5.43 (d, 1H), 7.28 (d, 1H), 7.69–7.77 (m, 2H), 7.84–7.88 (m, 2H).
2-(4-Oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione (13 g, 0.051 mol) was dissolved in ethyl acetate (250 ml) and placed in a Parr bottle. 10% Pd/C (1.5 g) was carefully added and the mixture was shaken under a pressure of 30 psi of hydrogen for 6.5 h (Parr apparatus). Filtration followed by evaporation of the ethyl acetate in vacuo afforded a crude 11.5 g of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione pure enough for the next step. Analytical pure compound could be obtained by purification of a small sample (250 mg) by column chromatography on silica gel, utilising a mixture of hexane/ethyl acetate as a gradient (from 100/0 to 50/50). Pure fractions were collected and the solvent evaporated in vacuo affording 142 mg (55%) of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
1H NMR (400 MHz, CDCl3) δ 2.30–2.68 (m, 4H), 3.62 (m, 1H), 3.74 (m, 1H), 4.00 (m, 2H), 7.75 (m, 2H), 7.88 (m, 2H).
To a mixture of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione (11.5 g, 44 mmol), tert-butyl cyanoacetate (6.9 g, 49 mmol) and elemental sulfur (1.6 g, 49 mmol) in ethanol (250 ml) was added morpholin (15 ml) and the resulting mixture was stirred at 50° C. for 16 h. The cooled reaction mixture was filtered and the precipitate filtered off and washed with diethyl ether and dried in vacuo affording 6.5 g (35%) of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
The filtrate was evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml) washed with water (2×100 ml), brine (100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 6.0 g (33%) of almost regioisomer pure 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
2-amino-5-(1,3-dioxo-1,3′-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester
1H NMR (300 MHz, CDCl3) δ1.50 (s, 9H), 2.54–2.63 (m, 1H), 2.84–2.90 (m, 1H), 3.79 (q, 1H), 3.96–4.04 (m, 2H), 4.48–4.62 (m, 2H), 5.91 (bs, 2H, NH2), 7.70 (m, 2H), 7.84 (m, 2H).
2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester
1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 2.71–2.90 (m, 2H), 3.67–3.77, (m, 2H), 4.02–4.15 (m, 2H), 4.90 (m, 1H), 6.04 (bs, 2H, NH2), 7.70 (m, 2H), 7.84 (m, 2H).
To a solution of 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (6.0 g, 0.014 mol) in ethanol (100 ml) was added hydrazine-hydrate (1.4 ml, 0.029 mol). The mixture was stirred at reflux temperature for 1 h. The cooled reaction mixture was filtered and the solvent evaporated in vacuo. The residue was dissolved in diethyl ether (200 ml) and washed with water (100 ml), brine (100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 2.9 g (71%) of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
To a ice cooled mixture of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1.4 g, 4.92 mmol), triethylamine (2 ml) in dichloromethane (100 ml) was added dropwise a solution of benzo[1,3]dioxole-5-carbonyl chloride (1.0 g, 5.41 mmol) in dichloromethane (25 ml) during 1.5 h. The ice cooled reaction mixture was stirred for an additional 0.5 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml) and washed with water (2×100 ml), brine (100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue (2 g) was subjected to flash column chromatography (1 l silicagel) using a mixture of ethyl acetate/hexane (1:2) as eluant. Pure fractions were collected affording after evaporation in vacuo 0.3 g (14%) of 2-amino-7-(((benzo[1,3]dioxole-5-carbonyl)amino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
TLC: Rf=0.44 (ethyl acetate/heptane 1:1)
A mixture of the above 2-amino-7-(((benzo[1,3]dioxole-5-carbonyl)amino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl, ester (0.3 g, 0.69 mmol), imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.16 g, 0.83 mmol) in dry tetrahydrofuran (50 ml) was stirred at room temperature for 16 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and washed with water (2×50 ml), brine (50 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue (0.35 g) was subjected to flash column chromatography (500 ml silicagel) using a mixture of ethyl acetate/hexane (1:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo. The residue was trituated with diethyl ether (5 ml), filtered off and dried in vacuo at 50° C. for 5 h which afforded 0.17 g (44%) of 7-(((benzo[1,3]dioxole-5-carbonyl)amino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
TLC: Rf=0.37 (ethyl acetate/heptane 1.1).
The above di-tert-butyl ester (0.17 g, 0.30 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane (20 ml). The reaction was stirred at room temperature for 5.5 h. The volatiles were evaporated in vacuo and the residue trituated with diethyl ether (10 ml). The precipitate was filtered off, washed with diethyl ether, dried in vacuo at 50° C. for 72 h which afforded 100 mg (74%) of the title compound as a solid.
M.p.: 277–230° C.
Calculated for C19H16N2O9S, 0.5×H2O; C, 49.89%; H, 3.75%; N, 6.12%. Found: C, 50.02%; H, 3.68%; N, 5.98%.
Example 29




7-[3-(2,4-Dimethoxy-phenyl)-ureidomethyl]-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (64 mg, 0.22 mmol) in dichloromethane (1 ml) was added 2,4-dimethoxyphenylisocyanate (40 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (30 ml), washed with saturated sodium carbonate (3×25 ml), brine (3×25 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to preparative thin layer chromatography (100% dichloromethane). Rf=0.8 was isolated and the solvent evaporated in vacuo which afforded 55 mg (53%) of 2-amino-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=9.6, 1H), 7.62 (d, J=8.1, 1H), 6.45 (m, 3H), 5.00 (bs, 2H), 4.68 (m, 1H), 4.12 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.76–3.67 (m, 1H), 3.30 (dd, J=14, 6.9, 1H), 2.76 (m, 2H), 1.55 (s, 9H).
MS: APCI (+): 464.3 (M+H).
To a solution of the above 2-amino-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (47 mg, 0.11 mmol) in dichloromethane (1 ml) was added triethylamine (28 μl, 0.22 mmol) and midazol-1-yl-oxo-acetic acid tert-butyl ester (40 mg, 0.22 mmol). The mixture allowed to stir at room temperature for 18 h. The volatiles were evaporated in vacuo and the residue diluted with ethyl acetate (35 ml). The organic phase was washed with saturated sodium carbonate (3×25 ml), brine (3×25 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo. The resultant oil was subjected to preparative thin layer chromatography (60% ethyl acetate/40% hexanes). Pure 2-(tert-butoxyoxalyl-amino)-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester 34 mg (58%) was isolated as an oil.
1H NMR (300 MHz, CDCl3) δ 12.49 (s, 1H), 7.70 (d, J=9.6, 1H), 6.62 (bs, 1H), 6.47 (m, 3H), 5.02 (bs, 1H), 4.84 (m, 1H), 4.19 (dm, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75–3.70 (m, 1H), 3.36 (dd, J=13.5, 7.5, 1H), 2.87 (m, 2H), 1.61 (s, 9H), 1.60 (s, 9H).
MS: APCI (+): 592.4 (M+H).
The above 2-(tert-butoxyoxalyl-amino)-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (34 mg) was dissolved in 20% trifluoroacetic acid in dichloromethane (2 ml) and stirred at room temperature for 3 hours. The volatiles were evaporated in vacuo and the residue was titurated with diethyl ether (2×), filtered off and washed with a small amount of dichloromethane which afforded after drying in vacuo 16 mg (89%) of the title compound as a solid.
1H NMR (300 MHz, CD3OD) δ 7.66 (d, J=9, 1H), 6.53 (d, J=2.7, 1H), 6.44 (dd, J=9, 2.7, 2H), 4.82 (m, 1H), 4.2 (m, 2H), 3.82 (s, 3H), 3.76 (s, 3H), 3.67 (dd, J=13, 4.5, 2H), 2.94 (m, 2H).
MS: APCI (+): 480.3 (M+H);
Example 30




2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3 carboxylic acid
A solution of glyoxylic acid ethyl ester, polymer form (2.02 g, 8.9 mmol) and (3-methoxy-1-methylene-allyloxy)-trimethyl-silane (1.9 ml, 8.9 mmol, Danishefsky's diene) in benzene (12 ml) was placed under nitrogen. Zinc chloride (0.5N in tetrahydrofuran, 8.9 ml, 4.45 mmol) was added and the reaction stirred at ambient temperature for 72 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo which afforded 1.2 g (75%) of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester as an oil.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=6, 1H), 5.48 (d, J=6, 1H), 5.01 (t, J=8, 1H), 4.28 (q, J=7, 2H), 2.85 (d, J=8, 2H), 1.29 (t, J=7, 3H).
To a solution of the above of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (1.0 g, 5.9 mmol) in ethyl acetate (12 ml) was added 10% palladium on activated carbon (0.15 g). The reaction was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 1.5 h. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography sing diethyl ether as eluant. Pure fractions were collected and the solvent evaporated in vacuo which affording 0.6 g (60%) of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl as an oil.
1H NMR (300 MHz, CDCl3) δ 4.41–4.35 (m, 1H), 4.26 (q, J=7, 2H), 3.81–3.70 (m, 1H), 2.73–2.58 (m, 3H), 2.44–2.36 (m, 1H), 1.29 (t, J=7, 3H).
To a solution of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl (0.6 g, 3.5 mmol) in absolute ethanol (6 ml) was added sulfur (0.12 g, 3.85 mmol) and tert-butyl cyanoacetate (0.64 g, 4.55 mmol). The solution was stirred under nitrogen in a 50° C. oil bath and morpholin (0.61 ml, 7.0 mmol) was added. The reaction was stirred for 18 h. and then cooled to ambient temperature and excess sulfur removed by filtration. The filtrate was concentrated in vacuo and reconstituted in ethyl acetate (50 ml). The organic phase was washed with brine (2×10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (20 to 25% gradient) as eluant. Pure fraction of the two isomers were collected and the solvent evaporated in vacuo which afforded 0.47 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (A) and 0.3 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (B) in 62% combined yield.
(A)
1H NMR (300 MHz, CDCl3) δ 5.96 (bs, 2H), 4.77–4.61 (m, 2H), 4.32–4.18 (m, 3H), 3.19–3.12 (m, 1H), 2.90–2.80 (m, 1H), 1.52 (s, 9H), 1.29 (t, J=7, 3H).
APCI-MS: [M+H]+=272.4 (loss of t-butyl)
(B)
1H NMR (300 MHz, CDCl3) δ5.10 (s, 1H), 4.28–4.13 (m, 3H), 3.98–3.91 (m, 1H), 2.82–2.76 (m, 2H), 1.51 (s, 9H), 1.31 (t, J=7, 3H).
APCI-MS: [M+H]+=272.4 (loss of t-butyl)
The above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (275 mg, 0.84 mmol) was dissolved in a mixture of ethanol (4 ml) and tetrahydrofuran (1 ml). Sodium hydroxide (1N, 1.6 ml, 1.68 mmol) was added and the reaction stirred at ambient temperature for 5 h. after which TLC analysis indicated that the reaction was complete. The reaction was monitored with a pH meter and neutralized with 1N hydrochloric acid until pH=6.9. The solution was concentrated in vacuo to give 2-amino-4±7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester as a solid. Sodium chloride remained as an impurity.
1H NMR (300 MHz, CD3OD) δ 4.67–4.54 (m, 2H), 4.00–3.95 (m, 1H), 3.20–3.12 (m, 1H), 2.74–2.63 (m, 1H), 1.54 (s, 9H).
APCI-MS: [M+H]+=300.0
To a solution of the above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) in distilled dichloromethane (4 ml) under nitrogen was added aniline (32 μl, 0.34 mmol) followed by 2,6-lutidine (0.11 ml, 0.93 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 51 mg (45%) of 2-amino-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.60 (d, 1H, J=7), 7.49 (d, 1H, =8), 7.34 (t, 1H, J=8), 7.32 (t, 1H, J=8), 7.13 (t, 1H, J=7), 6.03 (s, 2H), 4.82–4.73 (m, 2H), 4.25–4.22 (m, 1H), 3.43–3.38 (m, 1H), 2.79–2.72 (m, 1H), 1.54 (s, 9H).
APCI-MS: [M+H]+=375.5
To a solution of the above 2-amino-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (51 mg, 0.14 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (80 mg, 0.42 mmol) and triethylamine (38 μl, 0.28 mmol). The reaction was stirred for 4 h., concentrated in vacuo and reconstituted in ethyl acetate (25 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), brine (5 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 4% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 41 mg (26% over two steps) of 2-(tert-butoxyoxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 12.56 (s, 1H), 8.40 (s, 1H), 7.59 (d, J=8, 2H), 7.33 (t, J=8, 2H), 7.12 (t, J=7, 1H), 5.01–4.85 (m, 2H), 4.27–4.22 (m, 1H), 3.54–3.47 (m, 1H), 3.89–2.79 (m, 1H), 1.60 (s, 9H), 1.58 (s, 9H).
APCI-MS: [M+H]+=503.2
The above 2-(tert-butoxyoxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (37 mg, 0.074 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (3 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with ethyl ether and dried in vacuo to give 18 mg (62%) of the title compound.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.85 (s, 1H), 7.69 (d, J=8, 2H), 7.31 (t, J=8, 2H), 7.07 (t, J=7, 1H), 4.98 (d, J=15, 1H), 4.83 (d, J=15, 1H), 4.35–4.31 (m, 1H), 3.23 (d, J=17, 1H), 2.84 (dd, J=17, 10, 1H).
APCI-MS: [M+H]+=391.3
HPLC (254.4 nm): Rt=3.22 min, 100%
Example 31




5-Benzylcarbamoyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (101 mg, 0.34 mmol, prepared in Example 31) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.41 mmol) in distilled dichloromethane (4 ml) under nitrogen was added benzylamine (40 μl, 0.37 mmol) followed by 2,6-lutidine (0.12 ml, 1.02 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4) over sodium sulfate, filtered, and the solvent evaporated in vacuo to give 72 mg (56%) of 2-amino-5-benzylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (400 MHz, CDCl3) δ 7.36–7.28 (m, 5H), 4.66 (s, 2H), 4.44 (d, J=5, 2H), 4.17–4.13 (m, 1H), 3.40–3.33 (m, 1H), 2.75–2.66 (m, 1H), 1.54 (s, 9H).
APCI-MS: [M+H]+=389.5
To a solution of the above 2-amino-5-benzylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3,carboxylic acid tert-butyl ester (72 mg, 0.19 mmol) in distilled dichloromethane (4 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.11 g, 0.57 mmol) and triethylamine (51 μl, 0.38 mmol). The reaction was stirred for 4 h., concentrated in vacuo and reconstituted in ethyl acetate (25 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), brine (5 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (5 to 10% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 42 mg (24% over two steps) of 5-benzylcarbamoyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,carboxylic acid tert-butyl ester as an oil.
1H NMR (400 MHz, CDCl3) δ 12.56 (s, 1H), 7.37–7.29 (m, 5H), 6.97 (t, 1H, J=6), 4.89–4.77 (m, 2H), 4.58–4.46 (m, 2H), 4.20–4.16 (m, 1H), 3.50–3.44 (m, 1H), 2.84–2.76 (m, 1H), 1.61 (s, 9H), 1.60 (s, 9H).
APCI-MS: [M+H]+=517.3
The above 5-benzylcarbamoyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,carboxylic acid tert-butyl ester (36 mg, 0.07 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (3 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 14 mg (50%) of the title compound as a solid.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.48 (t, J=6, 1H), 7.31–7.20 (m; 5H), 4.91 (d, J=15, 1H), 4.76 (d, J=15, 1H), 4.32–4.29 (m, 2H), 4.20–4.16 (m, 1H); 3.22 (m, 1H, partially obscured by water), 2.70–2.63 (m, 1H).
APCI-MS: [M+H]+=405.2
HPLC (254.4 nm): Rt=3.06 min, 100%
Example 32




2-(Oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 7-ethyl ester
To a solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (60 mg, 0.18 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.11 g, 0.54 mmol) and triethylamine (50 μl, 0.36 mmol). The reaction was stirred for 4 h., concentrated in vacuo and reconstituted in ethyl acetate (20 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), brine (5 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 6% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 78 mg (95%) of 2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 12.54 (s, 1H), 5.28 (s, 1H), 4.27 (q, 2H, J=7), 4.25–4.18 (m, 1H), 4.04–3.96 (m, 1H), 2.96–2.80 (m, 2H), 1.60 (s, 9H), 1.57 (s, 9H).
LC-MS: Rt=3.97 min, [M+H]+=456.3
The above 2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (72 mg, 0.16 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (4 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 48 mg (88%) of the title compound as a solid.
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 5.47 (s, 1H), 4.19 (q, J=7, 2H), 3.98–3.94 (m, 2H), 2.90–2.78 (m, 2H), 1.23 (t, J=7, 3H).
APCI-MS: [M+H]+=344.2
HPLC (254.4 nm): Rt=2.82 min, 100%
Example 33




7-Benzylcarbamoyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (0.12 g, 0.37 mmol) in ethanol (3 ml) was added potassium hydroxide (56 mg, 1.0 mmol) dissolved in a minimum amount of water. The mixture was stirred for 24 h., then 1N hydrochloric acid was added until pH=7. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate (35 ml) and water (10 ml). The layers were separated and 1% hydrochloric acid (1 ml) was added to the aqueous layer. The aqueous layer was then extracted further with ethyl acetate (3×15 ml) and the combined organic extracts were washed with brine, dried (Na2SO4) and filtered. Triethylamine (3 drops) was added to the solution to stabilize the acid-sensitive compound. The solution was concentrated in vacuo affording 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester triethylamine salt (approximately 0.13 g) as a solid.
1H NMR (400 MHz, CDCl3) δ 5.01 (s, 1H), 4.28–4.23 (m, 1H), 3.90–3.85 (m, 1H), 2.88–2.71 (m, 3H), 1.56 (s, 9H).
A solution of the above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester triethylamine salt (0.12 g, 0.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71 mg, 0.36 mmol) was prepared in distilled acetonitrile under nitrogen. Benzylamine (36 μl, 0.33 mmol) was added followed by 2,6-lutidine (70 μl, 0.60 mmol). The reaction was stirred at ambient temperature for 18 h., then concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (2×5 ml), and brine (10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo which afforded crude 2-amino-7-benzylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester which was used without purification.
To a solution of the above crude 2-amino-7-benzylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (77 mg, 0.2 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.11 g, 0.6 mmol) and triethylamine (55 μl, 0.4 mmol). The reaction was stirred for 5 h., concentrated in vacuo and reconstituted in ethyl acetate (20 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), brine (5 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 5% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 29 mg (19% over two steps) of 7-benzylcarbamoyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (400 MHz, CDCl3) δ 12.49 (s, 1H), 7.35–7.26 (m, 5H), 6.96 (t, J=6, 1H), 5.20 (s, 1H), 4.55–4.41 (m, 2H), 4.22–4.17 (m, 1H), 3.87–3.81 (m, 1H), 2.97–2.84 (m, 2H), 1.61 (s, 9H), 1.59 (s, 9H).
APCI-MS: [M−H]−=516
The above 7-benzylcarbamoyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (29 mg, 0.06 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (2 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 18 mg (80%) of the title compound as an solid.
1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.67 (t, J=6, 1H), 7.30–7.21 (m, 5H), 5.23 (s, 1H), 4.31–4.28 (m, 2H), 4.13–4.10 (m, 1H), 3.88–3.85 (m, 1H), 2.86 (bs, 2H).
APCI-MS: [M+H]+=405
HPLC (254.4 nm): Rt=3.12 min, 94%
Example 34




7-((2-(4-Methanesulfonyl-phenyl)-acetylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of (4-methanesulfonyl-phenyl)-acetic acid (90.4 mg, 0.42 mmol) in a mixture of dichloromethane (3 ml) and N,N-dimethylformamide (1 ml) cooled at 0° C. was added diisopropyl-ethylamine (306 μl, 1.76 mmol), diisopropylazodicarboxylate (72 μl, 0.45 mmol) and 1-hydroxy-benzotriazole (56.6 mg, 0.42 mmol). After being stirred for 20 minutes, 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol) dissolved in dichloromethane (1 ml) was added via syringe. The reaction mixture was stirred for 18 h. while slowly warming to room temperature. The volatiles were evaporated in vacuo and the residue diluted with ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), 1% hydrochloric acid (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo. The resultant oil was subjected to preparative thin layer chromatography using a mixture of methanol/dichloromethane (1:9) as eluant. Fraction with Rf=0.5 was isolated which afforded after evaporating the solvent in vacuo 115 mg (69%) of 2-amino-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=8.7, 2H), 7.39 (d, J=7.5, 2H), 5.91 (bs, 2H), 4.65 (m, 1H), 4.09 (dt, J=7.8, 3.3, 1H), 3.85–3.65 (m, 2H), 3.61 (s, 2H), 3.45–3.38 (m, 2H), 3.05 (s, 3H), 2.75 (m, 2H), 1.56 (s, 9H).
MS: APCI (+): 481 (M+H).
To a solution of the above 2-amino-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (110 mg, 0.23 mmol) in dichloromethane (3 ml) was added triethylamine (96 μl, 0.69 mmol) and midazol-1-yl-oxo-acetic acid tert-butyl ester (134 mg, 0.69 mmol).
The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted in ethyl acetate (50 ml), washed with saturated sodium carbonate (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The resultant oil was subjected to preparative thin layer chromatography using a mixture of methanol/dichloromethane (1:9). Fraction with Rf=0.5 was collected and the solvent evaporated in vacuo affording 70 mg (50%) of 2-(tert-butoxyoxalyl-amino)-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (300 MHz, CDCl3) δ 12.49 (s, 1H), 7.88 (d, J=8.1, 2H), 7.46 (d, J=8.1, 2H), 5.88 (bs, 1H), 4.78 (m, 1H), 4.15 (dt, J=12, 4, 1H), 3.86–3.71 (m, 2H), 3.64 (s, 2H), 3.42–3.34 (m, 2H), 3.04 (s, 3H), 2.85 (m, 2H), 1.62 (s, 9H), 1.61 (s, 9H).
MS: APCI (+): 609 (M+H)[minor], 497 (−2 tert butyls)[major];
LC-MS: s, 99%
The above 2-(tert-butoxyoxalyl-amino)-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (60 mg, 0.098 mmol) was dissolved in 50% trifluoroacetic acid in dichloromethane (2 ml) and allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, the residue titurated with diethyl ether (3×), and dried in vacuo which afforded 45 mg (92%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.47 (m, 1H), 7.82 (d, J=7.8, 2H), 7.50 (d, J=7.8, 2H), 4.75 (bs, 1H), 4.10 (m, 1H), 3.69 (m, 1H), 3.60 (d, J=3.6, 2H), 3.52 (m, 1H), 3.35 (m, 2H), 3.18 (s, 3H), 2.83 (m, 2H).
MS: APCI (−): 495 (M−H); LC-MS: s, 95%.
Example 35




2-((3-Carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)carbamoyl)nicotinic acid
2-(tert-Butoxyoxalyl-amino)-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (164 mg, 0.58 mmol) was stirred for 20 h at 80° C. with furo[3,4-b]pyridine-5,7-dione (86.1 mg, 0.58 mmol) in a mixture of tetrahydrofuran (1.0 ml) and N,N-dimethylformamide (0.25 ml). The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate (50 ml) and washed with water (3×30 ml). The organic layer was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue (78 mg) was purified by preparative TLC (hexane/ethyl acetate, 50:50) which afforded 2 products: 2-((2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)carbamoyl)nicotinic acid (A) (27.9 mg, 11%) and 2-amino-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (B) (21.3 mg, 9%).
(A)
1H NMR (300 MHz, CDCl3): δ 9.02 (s, 1H), 8.74 (d, J=3.3, 1H), 8.14 (d, J=7.5, 1H), 7.40 (dd, J=4.8, J=5.1, 1H), 6.71 (m, 1H), 5.98 (s, 2H), 4.63 (s, 2H), 4.00 (m, 1H), 3.42 (m, 1H), 2.90 (dd, J=3.3, J=3.6, 1H), 2.59 (dd, J=11, J=1, 1H), 1.48 (s, 9H).
MS m/z 434 (M+);
(B)
1H NMR (300 MHz, CDCl3) δ8.99 (d, J=5.1, 1H), 8.20 (d, J=9, 1H), 7.64 (dd, J=5.7, 4.8, 1H), 5.94 (s, 2H), 4.60 (d, J=14, 1H), 4.51 (d, J=14, 1H), 4.05 (m, 2H), 3.87 (d, J=12.5, H), 2.92 (d, J=17, 1H), 2.61 (m, 1H), 1.53 (s, 9H).
MS: APCI (+): 416 (M+1)[minor], 360 (M-tert-butyl) [major].
To a solution of the above 2-((2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)carbamoyl)nicotinic acid (27.9 mg, 0.064 mmol) in tetrahydrofuran (2 ml) was added midazol-1-yl-oxo-acetic acid tert-butyl ester (38 mg, 0.193 mmol) and triethylamine (9 μl, 0.064 mmol). The resulting mixture was stirred at room temperature for 20 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (20 ml) and washed with water (3×10 ml). The extracts were dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by preparative TLC (0.5 mm, hexane/ethyl acetate, 1/1 to 2/3 gradient). After evaporation of the solvent in vacuo 917 mg (46%) of 2-(3-tert-butoxycarbonyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)carbamoyl)nicotinic acid was isolated as a solid.
1H NMR (300 MHz, CDCl3): δ 9.04 (s, 1H), 8.75 (s, 1H), 8.15 (d, J=7.5, 1H), 7.42 (dd, J=6.9, J=5.1, 1H), 6.73 (m, 1H), 4.81 (dd, J=15.3, J=14.4, 2H), 4.03 (m, 1H), 3.83 (m, 1H), 3.47 (m, 1H), 2.99 (d, J=17.1, 1H), 2.59 (dd, J=11.1, J=10.8, 1H), 1.61 (s, 9H), 1.48 (s, 9H).
MS: 506 (M−55).
The above 2-(3-tert-butoxycarbonyl-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)carbamoyl)nicotinic acid (13.1 mg, 0.023 mmol) was stirred in 50% trifluoroacetic acid in dichloromethane (2 ml) at room temperature for 7 h. The solvent was evaporated in vacuo which afforded 10 mg (96%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.77 (d, J=7.7, 1H), 8.16 (d, J=7.5, 1H), 7.60 (d, J=7.8, 1H), 4.88 (d, J=9, 1H), 4.76 (d, J=9, 1H), 3.96 (m, 1H), 3.02 (m, 1H), 2.78 (m, 1H). MS: 481 (M+33).
Example 36




7-(2,4-Dioxo-5-pyridin-2-ylmethylene-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a mixture of 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1.0 g, 2.42 mmol), 5-pyridin-2-ylmethylene-thiazolidine-2,4-dione (0.55 g, 2.66 mmol, prepared in a similar way as described in J. Med. Chem. 41 (10), 1619–1630 (1998)) and triphenylphosphine (0.7 g, 2.66 mmol) in dry tetrahydrofuran (75 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (420 μl ml, 2.66 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo, the resultant solid was washed with diethyl ether, filtered off and dried in vacuo at 50° C. for h affording 1.4 g (96%) of 2-(tert-butoxyoxalyl-amino)-7-(2,4-dioxo-5-pyridin-2-ylmethylene-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
TLC: Rf 0.46 (ethyl acetate/heptane 1:1).
The above di-tert-butyl ester (1.0 g, 1.66 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane (30 ml). The reaction was stirred at room temperature for 16 h. The volatiles were evaporated in vacuo and the residue trituated with diethyl ether (50 ml). The precipitate was filtered off, washed with diethyl ether, dried in vacuo at 50° C. for 16 h which afforded 0.8 g of semi pure title compound. The title compound (0.8 g) was suspended in ethyl-acetate (25 ml) and heated at reflux temperature for 0.5 h. Isopropanol (5 ml) was added and the mixture was cooled to room temperature the precipitate filtered off and dried in vacuo at 50° C. for 16 h which afforded 0.37 g (37%) of the title compound as a solid.
Calculated for C20H15N3O8S2, 0.5×H2O, 0.75×isopropanol; C, 49.17%; H, 4.08%; N, 7.73%. Found: C, 48.97%; H, 4.03%; N, 7.45%.
Example 37




7-(2,4-Dioxo-5-pyridin-2-ylmethyl-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 5-pyridin-2-ylmethylene-thiazolidine-2,4-dione (5.0 g, 0.024 mol, prepared in a similar way as described in J. Med. Chem. 41 (10), 1619–1630 (1998)) in tetrahydrofuran (300 ml) was added 10% palladium on carbon (1 g) and the resulting mixture was hydrogenated. After 50 ml of hydrogen was consumed and additional portion of 10% palladium on carbon (5 g) was added and the hydrogenation was continued at 50 psi for 16 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was subjected to flash column chromatography (1 l silicagel) using a mixture of ethyl acetate/hexane, (1:1) as eluant. Semi pure fractions were collected and the solvent evaporated in vacuo affording 0.8 g (16,%) of 5-pyridin-2-ylmethyl-thiazolidine-2,4-dione as a solid.
To a mixture of 2-(tert-butoxyoxalyl-amino)-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.7 g, 1.69 mmol), 5-pyridin-2-ylmethyl-thiazolidine-2,4-dione (0.36 g, 1.86 mmol) and triphenylphosphine (0.49 g, 1.86 mmol) in dry tetrahydrofuran (40 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo, the resultant residue was subjected to flash column chromatography (0.5 l silica gel) using a mixture of ethyl acetate/hexane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.6 g (59%) of 2-(tert-butoxyoxalyl-amino)-7-(2,4-dioxo-5-pyridin-2-ylmethyl-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
TLC: Rf=0.43 (ethyl acetate/heptane 1:1).
The above di-tert-butyl ester (0.5 g, 0.83 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane (25 ml). The reaction was stirred at room temperature for 16 h. The volatiles were evaporated in vacuo and the residue trituated with diethyl ether (20 ml). The precipitate was filtered off, washed with diethyl ether, dried in vacuo at 50° C. for 1 h which afforded 0.3 g of semi pure title compound. The title compound (0.3 g) was suspended in isopropanol (15 ml) and heated at reflux temperature for 5 min., cooled to room temperature and the precipitate filtered off and dried in vacuo at 50° C. for 16 h which afforded 0.2 g (49%) of the title compound as a solid.
M.p.: >250° C.;
Calculated for C20H17N3O8S2, 0.25×H2O; C, 48.43%; H, 3.56%; N, 8.47% Found: C, 48.41%; H, 3.57%; N, 8.10%
Example 38




7-(5-(4-Methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 37.
M.p.: 236–238° C.;
Calculated for C22H18N3O9S2, 0.5×H2O; C, 50.09%; H, 3.63%; N, 5.31%. Found: C, 49.92%; H, 3.59%; N, 5.18%.
Example 39




7-[5-(4-Acetylamino-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl]-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 37.
M.p.: >250° C.;
Calculated for C23H19N3O9S2, 2×H2O; C, 47.50%; H, 3.99%; N, 7.23%. Found: C, 47.60%; H, 3.45%; N, 6.80%.
Example 40




7-[5-(3,5-Dimethoxy-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl]-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 37.
1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.92 (s, 1H), 6.80 (d, J=1.8, 2H), 6.66 (t, J=2.1, 1H), 5.00 (m, 1H), 4.06 (bm, 2H), 3.81 (s, 6H), 3.71 (dd, J=6.6, 6, 2H), 2.83 (m, 2H).
MS: APCI (+): 549 (M+H); LC-MS; s, 90%.
Example 41




7-[5-(1H-Imidazol-4(5)-ylmethylene)-2,4-dioxo-thiazolidin-3-ylmethyl]-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 37.
M.P.: >250° C.;
Calculated for C18H14N4O8S2; C, 40.65%; H, 2.56%; N, 9.17%. Found: C, 40.54%; H, 2.55%; N, 9.46%.
Example 42




5-(1,3-Dioxo-4,7-epoxido-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-(tert-butoxyoxalyl-amino)-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.20 g, 0.48 mmol) in tetrahydrofuran (5 ml) was added 10-oxa-4-aza-tricyclo(5,2,1,0,2,6)decane-3,5-dione (81 mg, 0.48 mmol) and triphenylphosphine (126 mg, 0.48 mmol). The mixture was cooled to 0° C. and diisopropylazodicarboxylate (94.5 μl, 0.48 mmol) was added via syringe. The reaction was stirred for 18 h. while slowly warming to room temperature. The volatiles were evaporated in vacuo, and the residue diluted into ethyl acetate (50 ml), washed with saturated sodium bicarbonate (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The semi-solid residue was subjected to preparative thin layer chromatography using a mixture of ethyl acetate/hexanes (4:1) as eluant. Fraction with Rf=0.68 was isolated which afforded 64 mg (24%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-4,7-epoxido-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H NMR (300 MHz, CDCl3) δ 12.47 (s, 1H), 4.89 (m, 2H), 4.80–4.61 (m, 2H), 3.93–3.86 (m, 1H), 3.83–3.79 (m, 1H), 3.62–3.57 (dd, J=12.6, 3.6, 1H), 2.92 (q, 6.9, 2H), 2.60 (dd, J=17.1, 10.5, 2H), 1.85 (m, 2H), 1.60 (s, 18H).
MS: APCI (−): 561 (M−H).
The above 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-4,7-epoxido-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (51 mg) was dissolved in 50% trifluoroacetic acid in dichloromethane (5 ml) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and the residue titurated with diethyl ether (3×10 ml). The solid was filtered of and dried affording 30 mg (71%) of the title compound as a solid.
1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.68 (bs, 1H), 4.69 (s, 2H), 4.67 (d, J=15, 1H), 4.56 (d, J=15, 1H), 3.63 (bm, 1H), 3.50 (d, J=5, 1H), 3.46 (d, J=5, 1H), 3.08 (d, J=15, 2H), 2.94 (d, J=2.4, 1H), 2.89 (m, 1H), 1.64 (s, 4H).
MS: APCI (−): 449 (M−H);
LC-MS: s, 95%
Example 43




7-(((2R)-2-Amino-3-phenyl-propionylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid, trifluoroacetic acid salt
To a stirred solution of a mixture of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.7 g, 16 mmol) was added diisopropylethylamine (2.8 ml, 16 mmol) and succinimidyl-2,2,2-trichloroethylcarbonate (4.8 g, 16 mmol) portion wise. The reaction mixture was stirred at room temperature for 18 h, washed with saturated sodium hydrogen carbonate, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographyed on silica (90 g) using a mixture of ethyl acetate/heptane (1:1) as eluant. Pure fraction were collected and the solvent evaporated in vacuo affording 6.78 g of crude product which was dissolved in dichloromethane (5 ml) followed by heptane (30 ml) which was added as a top layer. After crystallisation and filtration 5.44 g (74%) of 2-amino-7-((2,2,2-trichloro-ethoxycarbonyl-amino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was obtained as an oil.
1H NMR (CDCl3) δ 1.55 (s, 9H), 2.78 (m, 2H), 3.32 (m, 1H), 3.62 (m, 1H), 3.72 (m, 1H), 4.15 (m, 1H), 4.68 (m, 1H), 4.71 (s, 2H), 6.00 (s, 2H).
The above 2-amino-7-((2,2,2-trichloro-ethoxycarbonylamino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.0 g, 8.0 mmol) was dissolved in a mixture of tetrahydrofuran (15 ml) and a aqueous phosphate buffer (pH 3; 5 ml) followed by addition of zinc (16 g, 0.244 mol). The reaction mixture was stirred for 6 h at room temperature at which time the solvent was removed in vacuo. To the residue was added diethyl ether (20 ml) and water (40 ml). Sodium carbonate was added to the aqueous phase until pH=8 and the aqueous phase was extracted with dichloromethane (3×). The combined organic phases were, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (90 g) using a mixture of dichloromethane/ethanol/25% ammonia in water 100:10:0.7 as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 1.52 g (61%) of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR (CDCl3) δ 1.45 (s, 9H), 2.69 (dt, 2H).
Calculated for C13H20N3O3S; C, 54.91%; H, 7.09%; N, 9.85%. Found: C, 54.53%; H, 7.19%; N, 9.61%.
LC-MS: Mw=285.2 Rt=4.14 min
To a solution of boc-D-phe-OH (0.28 g, 1.05 mmol) in dichloromethane (10 ml) was added 1-hydroxy benzotriazole (0.14 g, 1.05 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.18 g, 1.054-mmol). The reaction mixture was stirred for 15 min at room temperature. 2-Amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3′-carboxylic acid tert-butyl ester (0.30 g, 1.054 mmol) dissolved in dichloromethane (15 ml) was added. Ethyl diisopropylamine (0.18 ml, 1.05 mmol) was added and the reaction mixture was stirred over night at room temperature. The reaction was washed with 10% aqueous citric acid (15 ml), saturated aqueous sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent removed in vacuo affording 594 mg (100%) of 2-amino-7-(((1R)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
1H NMR(CDCl3) δ 1.42 (s, 9H), 1.55 (s, 9H), 2.73 (m, 2H), 3.05 (m, 2H), 3.16 (m, 1H), 4.06 (m, 1H), 4.32 (m, 1H), 5.05 (s, 1H), 6.01 (s, 2H), 6.10 (s, 1H), 7.20 (m, 5H).
LC-MS: Mw=532.2, Rt=7.1 1.
2-Amino-7-(((1R)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.58 g, 1.09 mmol) was dissolved in dichloromethane (15 ml). Triethylamine (0.3 ml, 2.18 mmol) was added and the reaction mixture was cooled with in a ice bath. Imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.43 g, 2.18 mmol) dissolved in dichloromethane (5 ml) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature diluted with dichloromethane (20 ml), washed with 1 N hydrochloric acid (15 ml), saturated sodium hydrogencarbonate (15 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography silica gel (40 g) using a mixture of ethyl acetate/heptane 1:1 as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 512 mg (69%) of 7-((1R)-(2-tert-butoxycarbonylamino-3-phenyl-propionylamino)methyl)-2-(tert-butoxyoxalylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (CDCl3) δ 1.42 (s, 9H), 1.59 (s, 9H), 1.61 (s, 9H), 2.86 (m, 2H), 3.02 (m, 2H), 3.15 (m, 1H), 3.64 (m, 1H), 3.87 (m, 1H), 4.09 (m, 1H), 4.28 (m, 1H), 4.51 (m, 1H), 4.67 (m, 1H), 5.10 (s, 1H), 6.00 (s, 1H), 7.20 (m, 5H), 12.5 (s, 1H).
7-((1R)-(2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyrran-3-carboxylic acid tert-butyl ester (0.51 g, 0.76 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added and the reaction mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo (stripped 3 times with dichloromethane) which afforded 314 mg (92%) of the title compound.
Calculated for C20H21N3O7S; 1×CF3COOH, 1×H2O; C, 45.60%; H, 4.17%; N, 7.25%. Found: C, 45.78%; H, 4.20%; N, 7.05%.
LC-MS: RT=3.61/RT=3.77 Mw=448.2
Example 44




7-((2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a mixture of Ac-D-Tyr-OH (235 mg, 1.05 mmol) dissolved in dichloromethane (10 ml) was added 1-hydroxybenzotriazole (0.14 g, 1.05 mmol), 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (0.20 g, 1.05 mmol) and the reaction mixture was stirred for 15 min at room temperature. 2-Amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.3 g, 1.05 mmol) dissolved in dichloromethane (10 ml) was added followed by N,N-diisopropyl-ethylamine (0.18 ml, 1.05 mmol). The resulting reaction mixture was stirred for 18 h at room temperature, diluted with dichloromethane (15 ml) was washed with 10% aqueous citric acid (25 ml), saturated sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (40 g) using ethyl acetate as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 304 mg (59%) of 7-((2-acetylamino-3-(4-hydroxy-phenyl)propionylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (CDCl3) double set of peaks from diastereomers; selected peaks: δ 1.55 (s, 9H), 1.95 (s, 3H), 2.74 (m, 2H), 2.92 (m, 2H), 3.23 (m, 1H), 3.63 (m, 2H), 6.05 (s, 2H).
LC-MS: Rt=5.17, Mw=490.4
7-((2-Acetylamino-3-(4-hydroxy-phenyl)propionylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.3 g, 0.61 mmol) was dissolved in dichloromethane (15 ml). Triethylamine (0.17 ml, 1.22 mmol) was added and the reaction mixture was cooled to 0° C. Imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.24, 1.22 mmol) dissolved in dichloromethane (10 ml) was added dropwise. The resulting reaction mixture was stirred at room temperature for 18 h. Dichloromethane (20 ml) was added and the mixture was washed with 1 N hydrochloric acid (15 ml), saturated sodium hydrogencarbonate (20 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (40 g) using ethyl acetate as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 208 mg (55%) of 7-((2-acetylamino-3-(4-hydroxy-phenyl)-propionylamino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
LC-MS: Mw=618.4, Rt=6.97
7-((2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.2 g, 0.32 mmol) was dissolved in dichloromethane (8 ml) and trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred 7 h at room temperature. The solvent was evaporated in vacuo (stripped 3 times with dichloromethane) which afforded 200 mg (100%) of the title compound.
Calculated for C22H23N3O9S, 3×H2O; C, 47.22%; H, 5.22%; N, 7.51%. Found: C, 47.05%; H, 4.88%; N, 7.39%.
LC-MS: Rt=3.64, Mw=506.4.
Example 45




7-((2-Acetylamino-3-methyl-butyrylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of Ac-D-Val-OH (0.17 g, 1.09 mmol) dissolved in dichloromethane (15 ml) was added N,N-dimethylformamide (1 Ml), 1-hydroxybenzotriazole (0.15 g, 1.09 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.21 g, 1.09 mmol). The reaction mixture was stirred for 15 min. at room temperature at which time a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.31 g, 1.09 mmol) in dichloromethane (10 ml) was added followed by N-N-diisopropylethylamine (0.186 ml, 1.09 mmol). The resulting mixture was stirred over night at room temperature diluted with dichloromethane (10 ml) washed with 10% aqueous citric acid (20 ml), sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent was evaporated in vacuo affording 415 mg (90%) of 7-((2-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (CDCl3) δ 0.88 (t, 3H), 0.98 (t, 2H), 1.55 (s, 9) 2.02 (d, 1H), 2.77 m, (2H), 3.40 (m, 1H), 4.14 (m, 1H).
To a mixture of 7-((2-acetylamino-3-methyl-butyrylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.4 g, 0.94 mmol) dissolved in dichloromethane (10 ml) and triethylamine (0.26 g, 1.87 mmol) cooled to 0° C. was added a solution of imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.37 g, 1.87 mmol) in dichloromethane (10 ml). The resulting mixture was stirred for 18 h at room temperature diluted with dichloromethane (20 ml) washed with 1N hydrochloric acid (15 ml), saturated sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent evaporated in vacuo which afforded 515 mg (97%) of 7-((2-acetylamino-3-methyl-butyrylamino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
LC-MS: Rt=7.11, Mw=554.4.
HPLC: Rt=34.16, Area (%)=100, %.
To a solution of the above 7-((2-acetylamino-3-methyl-butyrylamino)-methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.5 g, 0.90 mmol) dissolved in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) and the reaction mixture was stirred for 18 h at room temperature. Trifluoroacetic acid (4 ml) was added and the mixture was stirred for an additional 3 hours at room temperature. The volatiles were evaporated in vacuo (and stripped 3 times with dichloromethane) affording 282 mg (71%) of the title compound.
Calculated for C18H23N3O8S, 2×H2O; C, 45.28%; H, 5.70%; N, 8.80%. Found: C, 45.20%; H, 5.50%; N, 8.80%.
LC-MS: Rt=3.60, Mw=442.2
Example 46




2-(Oxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 25.
M.p.: 210–212° C.;
Calculated for C18H14N2O9S2, 0.5×H2O, 0.75×Ethyl acetate; C, 44.49%; H, 3.83%; N, 5.32%. Found: C, 44.70%; H, 3.61%; N, 4.90%.
Example 47




2-(Oxalyl-amino)-7-(3-oxo-3H-benzo[d]isoxazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in, Example 25.
M.p.: 236–237° C.;
Calculated for C18H14N2O8S, 0.3×H2O; C, 51.02%; H, 3.47%; N, 6.61%. Found: C, 51.16%; H, 3.47%; N, 6.31%.
Example 48




5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-ethyl ester
To a solution of 1,4-dioxa-8-aza-spiro[4,5]decane (51.5 g, 0.36 moles) in a mixture of dichloromethane (500 ml) and saturated sodium bicarbonate (500 ml) was added di-tert-butyldicarbonate (69.8 g, 0.32 moles) and the reaction was vigorously stirred for 3 hours and the layers separated. The organic layer was washed with 1N hydrochloric acid (2×150 ml), brine (100 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo affording 75.5 g (97%) of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester as a crystallizing oil.
1H NMR (400 MHz, CDCl3): δ 3.96 (s, 4H), 3.49 (bm, 4H), 1.65 (bm, 4H), 1.45 (s, 9H).
To the above 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (4.0 g, 16.4 mmol) dissolved in dry diethyl ether (32 ml) was added 2,2′ bipyridyl (1 mg) and the solution was cooled to −75° C. Tetramethyl-ethylenediamine (3.2 ml, 21.4 mmol) was added followed by dropwise addition of sec-butyl lithium (16.4 ml, 21.4 mmol, 1.3M in cyclohexane). The mixture was stirred at −75° C. for 10 min, then slowly warmed to −20° C. and stirred at that temperature for 0.5 h, then cooled to −30° C. At this temperature, formaldehyde was generated by heating paraformaldehyde at 150° C. and passed through the mixture with dry nitrogen until the color faded to off-white, at which time water (40 ml) was added. The layers were separated, and the aqueous layer was washed diethyl ether (2×50 ml). The combined organic extracts were washed 1N hydrochloric acid (2×75 ml), saturated sodium bicarbonate solution (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (2.9 g) was purified by silica gel chromatography (hexane/ethyl acetate, 10% ethyl acetate to 30% ethyl acetate, gradient). Pure fractions were collected and the solvent evaporated in vacuo affording 1.3 g (29%) of 7-hydroxy-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester as a thick oil.
1H NMR (400 MHz, CDCl3) δ 4.42 (bm, 1H), 4.08–3.96 (m, 5H), 3.96–3.88 (m, 1H), 3.78–3.70 (m, 1H), 3.30–3.16 (bm, 1H), 2.30–1.98 (bs, 1H), 1.96–1.78 (m, 2H), 1.74–1.64 (m, 2H), 1.49 (s, 9H).
To 7-hydroxy-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.4 g, 1.5 mmol) dissolved in dry tetrahydrofuran (20 ml) was added phthalimide (0.28 g, 1.9 mmol), triphenylphosphine (0.5 g, 1.9 mmol) and the mixture was cooled to 0° C. in an ice bath.
Diethylazodicarboxylate (0.29 ml, 1.82 mmol) was added dropwise and the mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexane/ethyl acetate, 18% ethyl acetate to 25% ethyl acetate, gradient). Pure fractions were collected and the solvent evaporated in vacuo affording 0.29 g (48%) of 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester.
1H NMR (400 MHz, CDCl3) δ 7.94–7.80 (bs, 2H), 7.80–7.64 (bd, 2H), 4.96–4.70 (2bs, 1H), 4.66–4.52 (m, 1H), 4.30–4.14 (bm, 1H), 4.12–4.04 (m, 2H), 4.04–3.94 (m, 2H), 3.56–3.32 (m, 2H), 2.04–1.92 (m, 1H), 1.90–1.60 (m, 4H), 1.22–1.0 (2bs, 9H).
MS: (M+1)=403, (M-Boc)=303.
To the above 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.1 g, 2.7 mmol) dissolved in dichloromethane (6 ml) was added 1.0 N hydrogen chloride in diethyl ether (50 ml) and the solution kept at ambient temperature for 62 h. The precipitate was filtered off and washed with diethyl ether and dried with nitrogen which afforded 0.83 g (90%) of 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione hydrochloride as a solid.
1H NMR (400 MHz, DMSO-d6) δ 9.2–8.8 (2bs, 2H), 7.8–8.1 (m, 2H), 4.1–3.6 (m, 5H), 2.9 (bs, 1H), 2.2–1.6 (m, 5H). MS: (M+1)=303.5.
To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.1 mmol) and ethyl chloroformate (0.24 ml, 2.5 mmol) in dry tetrahydrofuran (14 ml) cooled in an ice bath under nitrogen was added diisopropylethylamine (0.95 ml, 5.4 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between dichloromethane (25 ml) and 1N hydrochloric acid (25 ml). The layers were separated, and the aqueous layer extracted with dichloromethane (20 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was triturated with n-butylchloride, filtered and dried with nitrogen which afforded 0.47 g (61%) of 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid ethyl ester.
1H NMR (400 MHz, CDCl3) δ 7.9 (s, 2H), 7.7 (s, 2H), 4.9–4.7 (2bs, 1H), 4.7–4.5 (m, 1H) 4.3–3.9 (m, 5H), 3.9–3.6 (bs, 1H), 3.6–3.3 (m, 2H), 2.0–1.9 (m, 1H), 1.9–1.5 (m, 4H), 1.1–0.7 (2bs, 3H). MS: (M−1)=373.
A solution of the above 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid ethyl ester (0.44 g, 1.2 mmol) in a mixture of 1N hydrochloric acid (18 ml) and tetrahydrofuran (18 ml) was heated a 75° C. under nitrogen with stirring for 18 h. The tetrahydrofuran was removed in vacuo and the residue was extracted with dichloromethane (2×75 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo affording 0.42 g (>100%) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid ethyl ester as a solid.
1H NMR (400 MHz, CDCl3) δ 7.9 (s, 2H), 7.8 (s, 2H), 5.3–5.0 (bm, 1H), 4.6–4.2 (bm, 1H), 4.0 (m, 2H), 3.8–3.6 (bm, 3H), 2.8 (m, 1H), 2.7–2.4 (bm, 3H), 1.0 (bs, 3H).
MS: (M+1)=330.56.
A mixture of the above 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid ethyl ester (0.39 g, 1.2 mmol), tert-butyl cyanoacetate (0.22 g, 1.55 mmol), sulfur (42 mg, 1.3 mmol) in ethanol (1.5 ml) was degassed. To this mixture, under nitrogen, morpholine (205 μl) was added and the mixture was heated a 50° C. for 13 hours. The solvent was removed in vacuo. The residue (0.74 g) was purified by silica gel chromatography using a mixture of hexane/ethylacetate (7:3) as eluant. Pure fraction were collected and the solvent evaporated in vacuo. The residue (0.29 g) was titurated with acetonitrile, filtered, and dried with nitrogen affording 84 mg (15%) of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester.
1H MNR (400 MHz, CDCl3) δ 7.9–7.7 (2m, 4H), 6.0 (bs, 2H), 5.1–4.8 (bm, 1H), 4.8–4.5 (m, 1H), 4.5–4.2 (m, 1H), 4.1–3.4 (3m, 4H), 3.0 (m, 2H), 1.8–1.4 (m, 10H), 1.1–0.9 (m, 3H).
MS: (M+1)=486.
To the above 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (48 mg, 0.1 mmol) dissolved in dry tetrahydrofuran (1 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.4 ml) and the solution stirred for 18 h. at ambient temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (25 ml) and a saturated sodium bicarbonate solution (25 ml) was added. The layers were separated and the aqueous layer was extracted with dichloromethane (25 ml). The combined organic extracts were dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue (63 mg) was dissolved in ethyl acetate and passed through 1 g of silica gel and the solvent evaporated in vacuo affording 55 mg (90%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester as a solid.
The above 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (55 mg, 0.09 mmol) was dissolved in 50% trifluoroacetic acid in dichloromethane (2 ml) and stirred at ambient temperature for 18 h. The volatiles were removed in vacuo and the residue was purified by preparative hplc (column: Kromasil C18, 250×4.6 mm, flow: 2 ml/min, gradient: acetonitrile/water, 20% acetonitrile to 60% acetonitrile over 20 min.) affording after evaporation in vacuo 13.8 mg (31%) of the title compound as a solid. (KromasilTM available from e.g. Richard Scientific Inc, Novato Calif.
1H NMR (400 MHz, DMSO-d6) δ 14–13 (bs, 1H), 12.4 (s, 1H), 7.9 (s, 4H), 4.9 (m, 2H), 4.4 (m, 1H), 4.0–2.8 (m, 13H), 0.8 (m, 3H).
MS: (M+1)=502.
Example 49




5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (353 mg, 0.88 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (7 ml). The reaction was stirred for 5 minutes in the ice bath then another 3 hours at ambient temperature, after which it was concentrated in vacuo affording a solid residue. To the solid was added 2N hydrochloric acid (9 ml) and the mixture was heated at 50° C. (oil bath) with stirring for 24 h. The cooled reaction mixture was quenched with saturated sodium bicarbonate solution until the pH was basic. The aqueous layer was extracted with chloroform (3×20 ml) and the combined organic extracts dried (K2CO3), filtered, and the solvent evaporated in vacuo to give 205 mg (91%) of 2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione as a solid.
1H NMR (400 MHz, CDCl3) δ 7.90–7.83 (m, 2H), 7.78–7.71 (m, 2H), 3.81–3.73 (m, 2H), 3.43–3.35 (m, 1H), 3.30–3.22 (m, 1H), 2.83 (dt, J=13, 3, 1H), 2.46 (d, J=15, 1H), 2.42–2.32 (m, 2H), 2.21 (dd, J=14, 13, 1H).
APCI-MS: [M+H]+=259
The above 2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione (0.20 g, 0.76 mmol) was dissolved in dichloromethane (5 ml). Saturated sodium bicarbonate solution (5 ml) was added followed by di-tert-butyl dicarbonate (0.20 g, 0.91 mmol). The reaction was stirred vigorously for 16 h. after which the organic phase was separated. The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic extracts were dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (0 to 10% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.23 g (85%) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester.
1H NMR (400 MHz, CDCl3) δ 7.86 (bs, 2H), 7.72 (bs, 2H), 5.15–4.98 (m, 1H), 4.23–4.1.4 (m, 1H), 3.90 (t, J=12, 1H), 3.61–3.52 (m, 2H), 2.78–2.70 (m, 1H), 2.57–2.39 (m, 3H), 1.15 (s, 9H)
APCI-MS: [M+H]+=359
The above 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.43 g, 1.2 mmol) was dissolved in absolute ethanol (9 ml). To the solution was added sulfur (42 mg, 1.32 mmol) and tert-butyl cyanoacetate (0.22 g, 1.56 mmol). The mixture was placed under nitrogen and stirred in a 50° C. oil bath. Morpholine (0.21 ml, 2.4 mmol) was added and the reaction was stirred for 16 h. The precipitate formed was filtered off and washed with acetonitrile (2×3 ml) and dried which afforded 0.18 g of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (A) (30%). The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1:4 to 1:3 gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.3 g of a mixture of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester. HPLC purification of a small portion of the mixture gave 28 mg of pure 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (B).
(A):
1H NMR (400 MHz, CDCl3) δ 7.87–7.82 (m, 2H) 7.73–7.66 (m, 2H), 6.00 (bs, 2H), 5.02–4.87 (m, 1H), 4.72–4.21 (m, 2H), 4.03–3.93 (m, 1H), 3.51 (t, J=14, 1H), 2.97–2.91 (m, 2H), 1.56 (s, 9H), 1.12–1.09 (s, 9H).
LC-MS: Rt=3.96 min, [M+H]+=514.4
(B):
1H NMR (400 MHz, CDCl3) δ 7.88–7.82 (m, 2H), 7.74–7.66 (m, 2H), 5.39–5.19 (m, 1H), 4.30–4.02 (m, 2H), 3.78–3.70 (m, 1H), 3.33–3.18 (m, 1H), 2.86 (dd, J=18, 4, 1H), 2.75–2.61 (m, 1H), 1.54 (s, 9H), 1.13–1.05 (s, 9H).
LC-MS: Rt=4.01 min, [M+H]+=514.4
To a solution of the above 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (50 mg, 0.097 mmol) in dichloromethane (3 ml) was added midazol-1-yl-oxo-acetic acid tert-butyl ester (60 mg, 0.29 mmol). The reaction was placed under nitrogen and stirred for 3 hours at ambient temperature. The solution was concentrated in vacuo and the residue purified by silica gel chromatography using a 5% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 54 mg (87%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester.
1H NMR (400 MHz, CDCl3) δ 12.52 (s, 1H), 7.85 (bs, 2H), 7.74–7.67 (m, 2H), 5.08–4.92 (m, 1H), 4.93–4.40 (m, 2H), 3.97–3.87 (m, 1H), 3.53 (t, J=14, 1H), 3.11–2.99 (m, 2H), 1.62 (s, 18H), 1.14–1.12 (2s, 9H).
APCI-MS: [M−H]−=641
The above 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (54 mg, 0.084 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (2 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane, filtered off and dried in vacuo which afforded 41 mg (90%) of the title compound as a solid.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.36 (bs, 2H), 7.93–7.90 (m, 2H), 7.88–7.85 (m, 2H), 4.43 (d, J=16, 1H), 4.26 (d, J=16, 1H), 4.03–3.91 (m, 2H), 3.83–3.76 (m, 1H), 3.31 (dd, J=18, 4, 1H), 2.82 (dd, J=18, 10, 1H).
APCI-MS: [M+H]+=430
HPLC (254.4 nm): Rt=6.72 min, 98%
Example 50




(L)-5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of L-aspartic acid (120 g, 0.90 mol) in methanol (600 ml) cooled to −20° C. was added thionylchoride (93 ml, 1.29 mol) dropwise over 0.5 h. The cooling bath was removed and the mixture was stirred for 1 h, before diethyl ether (1.8 L, containing 50 ml 1 N hydrochloric acid in diethyl ether) was added upon cooling. The resulting precipitate was filtered off and washed with diethyl ether. The product was recrystallized twice:
First recrystallization: The product was dissolved in warm methanol (600 ml) and reprecipitated with 1.8 ml diethyl ether (containing 50 ml 1 N hydrochloric acid in diethyl ether).
Second recrystallization: The product was dissolved in warm methanol (250 ml) and reprecipitated with 1.0 m diethyl ether (containing 50 ml 1 N hydrochloric acid in diethyl ether).
This afforded 75 g (45%) of L-aspartic acid β-methyl ester hydrochloride as a solid.
To a solution of the above β-methyl ester (50 g, 0.27 mol) in water (120 ml) cooled to 0° C. was added triethylamine (95 ml, 0.68 mol) and methyl acrylate (74 ml, 0.82 mol). The reaction mixture was stirred for 3 hours before the cooling bath was removed. After stirring for an additional 1 h the mixture was washed with petrol ether (2×400 ml), before tert-butanol (40 ml) and di-tert-butyl dicarbonate (74 g, 0.34 mol) was added and the reaction mixture was stirred for 16 h. The mixture was washed with petrol ether (2×400 ml), cooled to 0° C. and the pH was adjusted to 3 with concentrated hydrochloric acid. After extraction with ethyl acetate (3×200 ml) the organic phase was washed with brine (200 ml), dried (MgSO4), filtered and the volatiles evaporated in vacuo. The residue was subjected to column chromatography on silicagel using a mixture of ethyl acetate/hexane/methanol/acetic acid (25:25:2.5:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo which afforded 60 g (66%) of 2-(tert-butoxycarbonyl-(2-methoxycarbonyl-ethyl)-amino)-succinic acid 4-methyl ester as a solid.
To a solution of the above di-ethyl ester (96.9 g, 0.29 mol) in dry degassed tetrahydrofuran (1.01) was added sodium methoxide (161 ml, 30% solution in methanol) and the reaction mixture was refluxed under nitrogen for 16 h with mechanical stirring. The reaction mixture was cooled to room temperature, the volatiles remove in vacuo until a wet cage was observed. Water (500 ml) was added and the reaction mixture was refluxed for 16 h. The remaining organic solvents were evaporated in vacuo before the pH was adjusted to 2.5 with concentrated hydrochloric acid. The aqueous phase was extracted with ethylacetate (3×3 ml) and the combined organic phases were washed with brine (100 ml), dried (MgSO4) and filtered. tert-Butyl amine (25.36 g, 0.350 mol) was added dropwise under stirring whereupon a off white precipitate was formed. The precipitate was filtered off and washed with ethyl acetate, dried in vacuo affording 74.4 g (81%) of 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester, tert-butyl amine salt as a solid.
Analytically pure compound can be obtained from recrystallisation of the crude product from ethanol-diisopropyl ether by heating the compound in ethanol (ca 100 ml per 10 g compound) and while still hot diisopropyl ether is added (ca 250 ml per 10 g compound). Yield in recrystallisation is approximately 50%.
A solution of the above 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester, tert-butyl amine salt (3.0 g, 9.48 mmol), tert-butyl cyanoacetate (2.01 g, 14.22 mmol), sulfur (0.456 g, 14.22 mmol) and diisopropyl-ethylamine (1.64 ml, 9.48 mmol) was heated to 50° C. under nitrogen for 12 h. The orange-yellow solution was allowed to cool to room temperature before a small precipitate was filtered off. The filtrate was evaporated in vacuo and the residue was divided between ethyl acetate (50 ml) and saturated ammonium chloride (100 ml). The aqueous phase was extracted with ethyl acetate (3×50 m) and the combined organic phases were washed with brine (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to column chromatography using a mixture of petrol ether/ethyl acetate/methanol (8:4:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 2.22 g (58%) of 2-amino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,5,6-tricarboxylic acid 3,6-di-tert-butyl ester as a solid.
To a solution of the above 3,5,6-tricarboxylic acid 3,6-di-tert-butyl ester (0.63 g, 1.58 mmol) in dimethoxyethane (10 ml) cooled to −20° C. was added N-methylmorpholine (174 ml, 1.58 mmol) followed by isobutylchloroformate (205 ml, 1.58 mmol) and the reaction mixture was stirred for two min. before a precipitate was filtered off. The precipitate was rapidly washed with dimethoxyethane (2×2.5 ml), recooled to −20° C. and a solution of sodium borohydride (90 mg, 2.37 mmol) in water (1 ml) was added in one lot. (Caution—gas evolution).
The reaction mixture was stirred until gas evolution ceases (app. 3 min.) and the mixture was poured into water (25 ml) and extracted with ethyl acetate (10 ml), washed with brine (5 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo affording 0.40 g (66%) of 2-amino-5-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
To a mixture of the above 2-amino-5-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (2.00 g, 5.20 mmol), phthalimide (0.92 g, 6.24 mmol) and triphenylphosphine (1.64 g, 6.24 mmol) in dry tetrahydrofuran (30 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (0.98 ml, 6.24 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. Next day the reaction mixture was again cooled to 0° C. and phthalimide (0.46 g, 3.12 mmol), triphenylphosphine (0.82 g, 3.12 mmol) and diethyl azodicarboxylate (DEAD) (0.49 ml, 3.12 mmol) was added in sequence and the reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in dichlorormethane (20 ml). The residue was subjected to flash column chromatography using a mixture of ethyl acetate/hexane (1:2) as eluant. Fractions were collected affording after evaporation in vacuo 1.0 g of the desired compound contaminated with phthalimide. Recrystallization from ethanol gave 0.23 g (9%) of pure 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
To the above di-tert-butyl ester (0.20 g, 0.39 mmol) dissolved in dichloromethane (4 ml) was added a mixture of imidazol-1-yl-oxo-acetic acid tert butyl ester (0.23 g, 1.17 mmol) in dichloromethane (1 ml) under nitrogen. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was added dichlorormethane (5 ml) and washed with 1% hydrochloric acid (10 ml), dried (Na2SO4), filtered and the organic phase evaporated in vacuo affording 0.25 g (100%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester.
The above tri-tert-butyl ester (0.25 g, 0.39 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (5 ml). The reaction was stirred at room temperature for 24 h. before diethyl ether (5 ml) was added. The precipitate was filtered off, washed with diethyl ether, dried in vacuo to give 0.150 g of a solid. NMR revealed the presence of a trace amount of material arising from incomplete deprotection. 0.100 g of the crude product was redissolved in 20% trifluoroacetic acid in dichloromethane (5 ml), and stirred at room temperature for 24 h. before diethyl ether (5 ml) was added. The product was filtered off and washed with diethyl ether and dried in vacuo to give 0.05 g (40%) of the title compound as a solid.
M.p.: dec.>240° C.
Calculated for C19H15N3O7S.1⁄3.C2HF3O2.1⁄2H2O; C, 49.58%; H, 3.46%; N, 8.82%. Found: C, 49.84%; H, 3.83%; N, 8.99%.
Example 51




7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of pure 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (28 mg, 0.057 mmol) in dichloromethane (2 ml) was added midazol-1-yl-oxo-acetic acid tert-butyl ester (35 mg, 0.17 mmol). The reaction was placed under nitrogen and stirred for 12 h. at ambient temperature. The volatiles were evaporated in vacuo and the residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:3) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 25 mg (67%) of 2-(tert-butoxyoxalyl-amino)-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as an oil.
1H NMR (400 MHz, CDCl3) δ 12.59–12.53 (bs, 1H), 7.89–7.84 (m, 2H), 7.75–7.67 (m, 2H), 5.61–5.41 (m, 1H), 4.36–4.15 (m, 1H), 4.12–4.06 (m, 1H), 3.90–3.82 (m, 1H), 3.34–3.21 (m, 1H), 2.99–2.93 (m, 1H), 2.84–2.68 (m, 1H), 1.62–1.59 (s, 18H), 1.12–1.06 (s, 9H).
The above 2-(tert-butoxyoxalyl-amino)-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (25 mg, 0.039 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (1.5 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane, filtered off and dried in vacuo to give 41 mg (85%) of the title compound as a solid.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.48 (bs, 2H), 7.95–7.91 (m, 2H), 7.89–7.84 (m, 2H), 4.89 (s, 1H), 4.15–4.07 (m, 2H), 3.43–3.28 (2m, 2H, partially obscured by water), 3.04 (bs, 2H).
LC-MS: Rt=1.51 min, [M−H]−=428.4
Example 52




5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.55 g, 3.85 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (15 ml). The reaction was stirred and allowed to slowly warm to ambient temperature during 3 hours. The solution was concentrated in vacuo to give crude 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione which was used directly in the following step (assumed 100% yield).
1H NMR (400 MHz, CDCl3) δ 9.26 (bs, 1H), 8.19 (bs, 1H), 7.78–7.75 (m, 2H), 7.74–7.71 (m, 2H), 4.11–3.98 (m, 5H), 3.90–3.79 (m, 3H), 3.26–3.17 (m, 1H), 2.10–2.00 (m, 3H), 1.92–1.88 (m, 1H).
To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (3.85 mmol) in absolute ethanol (25 ml) was added hydrazine (0.36 ml, 11.55 mmol). The reaction was stirred at 80° C. (oil bath) for 6 h., then cooled to ambient temperature and stirred for an additional 12 h. The thick precipitate was filtered off and washed with ethanol. The filtrate was concentrated in vacuo and reconstituted in dichloromethane (20 ml), forming a small amount of a second precipitate which was filtered off. The filtrate was evaporated in vacuo and the resulting oil was dissolved in water (10 ml) and basified with 1N sodium hydroxide until pH=10. The aqueous layer was extracted with 20% isopropyl alcohol/chloroform (12×40 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent evaporated in vacuo affording 0.42 g (63%) of (1,4-dioxa-8-aza-spiro[4.5]dec-7-yl)methylamine as an oil.
1H NMR (300 MHz, CDCl3) δ 3.94 (bs, 4H), 3.11–3.05 (m, 1H), 2.81 (dt, J=12, 3, 1H), 2.76–2.65 (m, 2H), 2.58–2.50 (m, 1H), 1.70–1.57 (m, 3H), 1.31 (t, J=12, 1H).
APCI-MS: [M+H]+=173.2
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.51 g, 3.09 mmol) in anhydrous N,N-dimethylformamide (7 ml) under nitrogen was added sodium hydride (130 mg, 3.25 mmol). Immediate evolution of gas and bright yellow color was observed. The mixture was stirred for 5 minutes after which benzyl bromide (1.8 ml, 15.45 mmol) was added. The reaction was stirred for 72 h. Saturated sodium bicarbonate (2 ml) was added and the mixture stirred for 2 minutes, diluted in ethyl acetate (35 ml) and washed with saturated sodium bicarbonate (5 ml), 1N hydrochloric acid (5 ml), and brine (2×5 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. To the crude material was added hexane and the formed precipitate was filtered off, washed further with hexane and dried in vacuo to give 0.54 g (69%) of 4-(benzyloxy)-isobenzofuran-1,3-dione as a solid.
1H NMR (300 MHz, CDCl3) δ 7.74 (t, 1H, J=8 Hz), 7.54 (d, 1H, J=8 Hz), 7.47–7.29 (m, 6H), 5.36 (s, 2H).
A solution of (1,4-dioxa-8-aza-spiro[4.5]dec-7-yl)methylamine (0.19 g, 1.1 mmol) and 4-(benzyloxy)-isobenzofuran-1,3-dione (0.27 g, 1.05 mmol) was prepared in a mixture of distilled dichloromethane (3 ml) and anhydrous N,N-dimethylformamide (2.5 ml) under nitrogen. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.21 mmol) was added followed by triethylamine (0.46 ml, 3.3 mmol) and the reaction stirred at ambient temperature for 18 h. The solution was concentrated in vacuo and the residue diluted with ethyl acetate (25 ml) and washed with water (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was evaporated in vacuo and the residue purified by silica gel chromatography using a mixture of 5% methanol/dichloromethane/1% triethylamine as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.22 g (50%) of 4-benzyloxy-2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione as a semi-solid.
1H NMR (400 MHz, CDCl3) δ7.57 (t, J=8, 1H), 7.48 (d, J=7, 2H), 7.42–7.29 (m, 4H), 7.18 (d, J=8, 1H), 5.31 (s, 2H), 3.94–3.90 (m, 4H), 3.65 (d, J=6, 2H), 3.16–3.09 (m, 1H), 3.07–3.02 (m, 1H), 2.76 (dt, J=13, 3, 1H), 1.78 (d, J=12, 1H), 1.64–1.54 (m, 3H), 1.37 (t, J=12, 1H), 1.08 (t, J=7, 1H).
LC-MS: Rt=2.59 min, [M+H]+=409.2
To a solution of the above 4-benzyloxy-2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (0.22 g, 0.54 mmol) in 1,4-dioxane (4 ml) was added 4N hydrochloric acid (4 ml) and the reaction stirred in a 65° C. (oil bath) for 6 h. The mixture was basified with saturated sodium bicarbonate until pH=8 and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording crude 4-benzyloxy-2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione as an oil. Which was used without further purification or characterization.
The above crude 4-benzyloxy-2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione (0.17 g, 0.47 mmol) was dissolved in dichloromethane (4 ml). Saturated sodium bicarbonate (4 ml) was added followed by di-tert-butyl dicarbonate (0.11 g, 0.52 mmol). The reaction was stirred vigorously for 16 h., then the layers were separated. The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic phases were dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1.2) as eluant. Pure fractions were collected and the solvent was evaporated in vacuo affording 0.14 g (64%) of 2-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester.
1H NMR (400 MHz, CDCl3) δ 7.57 (bs, 1H), 7.47–7.31 (m, 6H), 7.18 (bs, 1H), 5.34 (s, 2H), 5.03 (bs, 1H), 4.45–4.14 (m, 1H), 3.89 (t, J=12, 1H), 3.55 (bs, 2H), 2.76–2.71 (m, 1H), 2.57–2.38 (m, 3H), 1.17 (s, 9H).
A solution of 2-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.14 g, 0.30 mmol), sulfur (10.6 mg, 0.33 mmol), and tert-butyl cyanoacetate (55 mg, 0.39 mmol) in absolute ethanol (4 ml) was stirred at 50° C. (oil bath). Morpholine (53 μl, 0.6 mmol) was added and the reaction placed under nitrogen and stirred for 16 h. The solution was cooled to ambient temperature, concentrated in vacuo and the residue purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (0 to 5% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording a mixture of regioisomers 0.15 g (80%) of 2-amino-5-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-amino-7-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester which were not separable by chromatography.
To a solution of the above mixture of 2-amino-5-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-amino-7-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (0.15 g, 0.24 mmol) in distilled dichloromethane (4 ml) under nitrogen was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.14 g, 0.72 mmol) and the reaction mixture was stirred at ambient temperature for 1.5 h. The volatiles were evaporated in vacuo and the crude residue was purified by silica gel chromatography using dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 50 mg of 2-(tert-butoxyoxalyl-amino)- (4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (A) and 50 mg of 2-(tert-butoxyoxalyl-amino)-7-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (B). Another 50 mg remained as a mixture of the two isomers (A) and (B).
(A):
1H NMR (300 μMHz, CDCl3) δ 12.52 (s, 1H), 7.60–7.31 (m, 7H), 7.20–7.10 (m, 1H), 5.33 (s, 2H), 5.05–4.38 (m, 3H), 3.96–3.83 (m, 1H), 3.52–3.41 (m, 1H), 3.01 (bs, 2H), 1.60 (s, 9H), 1.59 (s, 9H), 1.17–1.14 (s, 9H).
LC-MS: Rt=4.93 min, [M+H]+=748.1
(B):
1H NMR (300 MHz, CDCl3) δ 12.58–12.52 (s, 1H), 7.60–7.30 (m, 7H), 7.20–7.10 (m, 1H), 5.60–5.39 (m, 1H), 5.34 (s, 2H), 4.36–4.02 (m, 2H), 3.86–3.75 (m, 1H), 3.33–3.18 (m, 1H), 2.97–2.90 (m, 1H), 2.83–2.68 (m, 1H), 1.60 (s, 9H), 1.58–1.57 (s, 9H), 1.15–1.09 (s, 9H)
LC-MS: Rt=4.93 min, [M+H]+=748.1
The above 2-(tert-butoxyoxalyl-amino)-5-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (50 mg, 0.067 mmol) was dissolved in a mixture of ethyl acetate/ethanol (3 ml, 1:1). Palladium on activated carbon (10%, 10 mg) was added and the solution degassed and stirred under hydrogen (1 atm.) for 72 h. TLC analysis indicated that the reaction was incomplete. The mixture was filtered through celite and the filter cake washed with hot ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (0 to 5% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 15 mg (30%) of 2-(tert-butoxyoxalyl-amino)-5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester.
1H NMR (300 MHz, CDCl3) δ 12.50 (s, 1H), 7.61–7.51 (m, 1H), 7.39–7.34 (m, 1H), 7.17–7.09 (m, 1H), 5.04–4.64 (m, 2H), 4.49–4.34 (m, 1H), 3.90–3.78 (m, 1H), 3.51–3.42 (m, 1H), 3.02 (bs, 2H), 1.60 (s, 18H), 1.17–1.14 (2s, 9H).
The above 2-(tert-butoxyoxalyl-amino)-5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (15 mg, 0.023 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (2 ml). The reaction was stirred at ambient temperature for 12 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo affording 6 mg (47%) of the title compound.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 11.17 (s, 1H), 9.25 (bs, 2H), 7.64 (t, J=8, 1H), 7.32 (d, J=8, 1H), 7.24 (d, J=8, 1H), 4.41–4.23 (m, 2H), 3.96–3.71 (m, 3H), 3.5–3.2 (obscured by water, 1H), 2.83–2.75 (m, 1H).
LC-MS: Rt=1.53 min [M+H]+=446.2
Example 53




2-(Oxalyl-amino)-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 h. cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1–2%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89%) of 2-bromomethyl-benzoic acid methyl ester as a solid.
1H NMR (CDCl3): δ 7.97 (d, 1H, J=7.6 Hz), 7.45–7.52 (m, 2H), 7.38 (dt, 1H, J=1.2, 7.6 Hz), 4.96 (s, 2H), 3.95 (s, 1H).
To a solution of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (100 mg, 0.20 mmol) and pyridine (0.18 ml, 2.0 mmol) in acetonitrile (1 ml) at room temperature was added benzyl chloroformate (0.28 ml, 2.0 mmol) in 10 aliquots over 48 h. The solution was then taken into ethyl acetate (30 ml), washed with 0.5 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate (3×10 ml), brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The resulting oil crystallized upon standing for 2 days. The precipitate was filtered off and washed with diethyl ether (3×1 ml) affording after drying in vacuo 59 mg (47,%) of 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
1H NMR (CDCl3): δ 10.60 (s, 1H), 7.60–7.92 (m, 4H), 7.38 (m, 5H), 5.26 (s, 2H), 4.30–5.10 (m, 3H), 3.40–4.00 (m, 2H), 1.57 (m, 9H), 1.15 (m, 9H).
To a solution of 1N hydrochloric acid in ethyl acetate (1.0 ml) was added 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (52 mg, 0.08 mmol). The solution was stirred at room temperature for 48 h. A precipitate was filtered off which afforded 42 mg (90%) of 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride as a solid.
1H NMR (DMSO-d6): 810.45 (s, 1H), 9.40 (s, 1H), 9.25 (s, 1H), 7.89 (m, 4H), 7.39 (m, 5H), 5.22 (s, 2H), 4.39 (d, 1H, J=15 Hz), 4.28 (m, 1H), 3.95 (m, 2H), 3.79 (m, 1H), 3.20 (m, 1H), 2.70 (m, 1H), 1.48 (s, 9H).
To a solution of the above 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride (42 mg, 0.072 mmol) in ethanol (0.5 ml) was added hydrazine (68 μl, 0.22 mmol). The solution was stirred at 80° C. for 5 h. and at room temperature for 16 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was extracted with dichloromethane (5×1 ml). The combined dichloromethane washes were evaporated in vacuo affording 20 mg (67%) of 5-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H NMR (CDCl3): δ 10.55 (bs, 1H), 7.37 (m, 5H), 5.23 (s, 2H), 3.92 (s, 2H), 2.60–3.10 (m, 3H), 1.53 (s, 9H).
To a solution of the above 5-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (20 mg, 0.048 mmol) in acetonitrile (1 ml) at 0° C. was added diisopropylethylamine (18 μl, 0.15 mmol) and 2-bromomethyl-benzoic acid methyl (12 mg, 0.048 mmol). The solution was stirred at 0° C. for 3 hours and at room temperature for 16 h. Di-tert-butyl dicarbonate (21 mg, 0.096 mmol) was then added to the solution. The solution was then stirred at room temperature for 16 h. The solution was taken into ethyl acetate (30 ml), washed with 0.5 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate (3×10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The solid residue was purified by silica gel chromatography using a 5% mixture of ethyl acetate/hexane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 10 mg (33%) of 2-benzyloxycarbonylamino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
1H NMR (CDCl3): δ 10.59 (s, 1H), 7.81 (m, 1H), 7.52 (m, 1H), 7.39 (m, 7H), 5.25 (s, 1H), 4.22–5.00 (m, 4H), 4.40–4.80 (m, 2H), 2.80–3.10 (m, 2H), 1.55 (s, 9H), 1.25 (s, 9H).
To a solution of the above 2-benzyloxycarbonylamino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (9 mg, 0.014 mmol) in methanol (2 ml) was added 10% Pd/C (4 mg). The mixture was stirred under hydrogen (1 atm.) for 3 hours and then filtered. The filtrate was evaporated in vacuo affording 6 mg (93%) of 2-amino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
1H NMR (CDCl3): δ 7.80 (m, 1H), 7.50 (m, 1H), 7.44 (m, 2H), 4.22–5.00 (m, 4H), 4.40–4.80 (m, 2H), 2.80–3.10 (m, 2H), 1.63 (s, 9H), 1.25 (s, 9H).
To a solution of the above 2-amino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (6 mg, 0.013 mmol) in acetonitrile (0.5 ml) at room temperature was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (27 mg, 0.13 mmol). The solution was stirred for 3 hours at room temperature and then diluted with ethyl acetate (20 ml), washed with 0.5 N hydrochloric acid (2×5 ml), saturated sodium bicarbonate (2×5 ml), brine (5 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo: The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (10–25% gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 4 mg (50%) of 2-(tert-butoxyoxalyl-amino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
1H NMR (CDCl3): δ 12.49 (s, 1H), 7.80 (m, 1H), 7.50 (m, 1H), 7.44 (m, 2H), 4.22–5.00 (m, 4H), 4.20–4.90 (m, 2H), 2.90–3.20 (m, 2H), 1.63 (s, 9H), 1.60 (s, 9H), 1.25 (s, 9H).
Example 55




2-(Oxalyl-amino)-7-(1,1,3-trioxo-5-phenyl-1,3-dihydro-isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1,1-dioxo-5-phenyl-1,2-dihydro-1H-isothiazol-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
1H-NMR (DMSO-d6) δ 2.85 (bs, 2H), 3.75 (m, 1H), 3.92 (dd, 1H), 4.10 (m, 2H), 5.08 (m, 1H), 7.64 (m, 3H), 7.69 (s, 1H), 7.92 (m, 2H), 12.35 (s, 1H, NHCO).
LC-MS: Rt=4.90 min, m/z: 493 [M+H]+
Example 56




7-(1,1-Dioxo-5-phenyl-1H-isothiazol-3-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1,1-dioxo-5-phenyl-1,2-dihydro-1H-isothiazol-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
1H-NMR (DMSO-d6) δ 2.86 (bs, 2H), 3.79 (m, 1H), 4.13 (m, 1H), 4.75 (m, 2H), 5.17 (bs, 1H), 7.60 (m, 3H), 7.70 (s, 1H), 7.88 (m, 2H), 12.35 (s, 1H, NHCO).
LC-MS: Rt=4.78 min, m/z: 493 [M+H]+
Example 57




2-(Oxalyl-amino)-5-(1,1,3-trioxo-5-phenyl-1,3-dihydro-isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1,1-dioxo-5-phenyl-1,2-dihydro-1H-isothiazol-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
1H-NMR (DMSO-d6) δ 2.62 (dd, 1H), 3.05 (d, 1H), 3.88 (m, 2H), 3.98 (m, 1H), 4.60–4.86 (dd, 2H), 7.6.6 (m, 4H), 7.93 (m, 2H), 12.3 (s, 1H, NHCO).
Example 58




5-(1,1-Dioxo-5-phenyl-1H-isothiazol-3-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1,1-dioxo-5-phenyl-1,2-dihydro-1H-isothiazol-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
Mp.: 230–232° C.;
Calculated for C20H16N2O9S2, 1×H2O; C, 47.06%; H, 3.55%; N, 5.49%. Found: C, 46.88%; H, 3.44%; N, 5.45%.
Example 59




5-(6-Chloro-1,1,3-trioxo-2,3-dihydro-4H-thieno[3,2-e]-1,2,4-thiadiazin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1,1-dioxide-6-chloro-2,3-dihydro-4H-thieno[3,2-e]-1,2,4-thiadiazine-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
1H-NMR (DMSO-d6) δ 2.60 (dd, 1H), 2.98 (d, 1H), 3.87–3.96 (m, 2H), 4.04 (m, 1H), 4.56–4.82 (dd, 2H), 7.0 (s, 1H), 11.95 (s, 1H, NHCO), 12.3 (s, 1H, NHCO).
Example 60




5-(6-Chloro-1,1-dioxo-4H-thieno[3,2-e]-1,2,4-thiadiazine-3-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1,1-dioxide-6-chloro-2,3-dihydro-4H-thieno[3,2-e]-1,2,4-thiadiazine-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
Mp.: >250° C.;
Calculated for C16H12ClN3O9S3, 0.75×H2O; C, 35.89%; H, 2.54%; N, 7.85% Found: C, 35.84%; H, 2.36%; N, 7.74%.
Example 61




7-(1,3-Dioxo-1,3-dihydro-benzo[d]isothiazol-2-ylmethyl)-2-(oxalyl-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1-oxo-1,2-dihydro-1H-benzo[d]isothiazol-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
LC-MS: Rt=3.82 min, m/z: 451 [M+H]+
Example 62




5-(1,3-Dioxo-1,3-dihydro-benzo[d]isothiazol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 1-oxo-1,2-dihydro-1H-benzo[d]isothiazol-3-one as starting material. O- and N-alkylated products were separated by column chromatography.
Mp.: 230–231° C.;
Calculated for C18H14N2O8S2, 0.5×H2O; C, 47.06%; H, 3.29%; N, 6.10% Found: C, 46.94%; H, 3.42%; N, 6.26%.
Example 63




5-(5-Benzyl-1,1-dioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-benzyl-[1,2,5]thiadiazolidine 1,1-dioxide as starting material.
Mp.: 188–192° C.;
LC-MS: Rt=5.00 min, m/z: 496 [M+H]+
Example 64




5-(5-Ethyl-1,1-dioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 23 using 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-ethyl-[1,2,5]thiadiazolidine 1,1-dioxide as starting material.
LC-MS: Rt=4.18 min, m/z: 434 [M+H]+
Example 65




2-(Oxalyl-amino)-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.38 mmol) and N,N-diisopropylethylamine (72 μL, 0.41 mmol) in acetonitrile (6 ml) at 0° C. was added 2-bromomethyl-benzoic acid methyl ester (43 mg, 0.19 mmol). The reaction mixture was stirred for 16 hours and the solvent evaporated in vacuo. The residue was diluted in ethyl acetate (50 ml), washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo, which afforded 50 mg (68%) of 2-amino-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 7.86 (d, 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 7.45 (t, 2H, J=8 Hz), 4.88 (dt, 1H, J=6, 2 Hz), 4.68 (d, 1H, J=17 Hz), 4.48 (d, 1H, J=17 Hz), 4.25–4.10 (m, 1H), 4.03 (dd, 1H, J=17 and J=3 Hz), 3.80–3.75 (m, 2H), 2.92–2.70 (m, 2H), 1.54 (s, 9H).
To a solution of 2-amino-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol) in tetrahydrofuran (1 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (100 mg, 0.51 mmol). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was taken into ethyl acetate (50 ml), washed with saturated sodium bicarbonate and brine, dried (Na2SO4) and filtered. The solvent was removed in vacuo and the residue was chromatographed using a mixture of 10% ethyl acetate/dichloromethane as eluent, which afforded 55 mg (83%) of 2-(tert-butoxyoxalyl-amino)-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.59 (s, 1H), 7.88 (d, 1H, J=7 Hz), 7.54 (t, 1H, J=7 Hz), 7.46 (t, 2H, J=7 Hz), 5.04 (dd, 1H, J=6 Hz and J=2 Hz), 4.69 (d, 1H, J=17 Hz), 4.46 (d, 1H, J=17 Hz), 4.26–4.10 (m, 2H), 3.77 (dd, 1H, J=9 Hz and J=3 Hz), 3.70 (dd, 1H, J=15 Hz and J=9 Hz), 3.02–2.80 (m, 2H), 1.55 (s, 18H).
A solution of 2-(tert-butoxyoxalyl-amino)-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (55 mg, 0.11 mmol) in 50% trifluoroacetic acid/dichloromethane (2 ml) was stirred for 16 hours. The volatiles were removed in vacuo and the residue was washed with dichloromethane and dried, which afforded 29 mg (50%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6) δ 12.35 (s, 1H), 7.70 (d, 1H, J=8 Hz), 7.61 (d, 1H, J=3 Hz), 7.52–7.47 (m, 2H), 5.04 (s, 1H), 4.59 (d, 1H, J=18 Hz), 4.58 (d, 1H, J=18 Hz), 4.19–4.08 (m, 1H), 3.88 (d, 1H, J=6 Hz), 3.78–3.66 (m, 1H), 3.38 (q, 1H, J=7 Hz), 2.85 (s, 2H);
LC-MS: Rt=2.12 min, m/z: 417 [M+H]+
Example 66




2-(Oxalyl-amino)-5-(2,2,2-trifluoro-acetoxymethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
2-(tert-Butoxyoxalyl-amino)-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.5 g, 1.21 mmol) was dissolved in dichloromethane (9 ml) and trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred 64 hours at room temperature. The precipitate was filtered off and washed with diethyl ether and dried in vacuo at 50° C. for 4 hours, which afforded 180 mg (50%) of the title compound as a solid.
Mp.: 231–233° C.;
Calculated for C13H10F3NO8S; C, 39.30%; H, 2.56%; N, 3.57%. Found: C, 39.30%; H, 2.54%; N, 3.53%.
Example 67




5-(((Benzo[1,3]dioxol-5-ylmethyl)-amino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of oxalyl chloride (1 ml, 11.13 mmol) in dichloromethane (40 ml) cooled to −78° C. under an atmosphere of nitrogen was added dropwise a solution of dimethylsulfoxide (1.6 ml, 21.78 mmol) in dichloromethane (16 ml) during 5 min. After stirring for 15 min at −78° C. a solution of 2-(tert-butoxyoxalyl-amino)-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2.0 g, 4.84 mmol) in dichloromethane (30 ml) was added dropwise and the resulting mixture was stirred for 0.5 hour at −78° C. N,N-Diisopropylethylamine (4.2 ml, 24.18 mmol) was added and the reaction mixture allowed reaching room temperature at which time heptane (700 ml) was added. The mixture was filtered through anhydrous sodium sulfate and the solvent evaporated in vacuo. The residue (2.71 g) was purified on column chromatography using a mixture of ethyl acetate/heptane (1:4) as eluent which afforded 0.93 g (47%) of 2-(tert-butoxyoxalyl-amino)-5-formyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
To a mixture of 2-(tert-butoxyoxalyl-amino)-5-formyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.46 g, 1.12 mmol) and piperonylamine (145 μl, 1.12 mmol) in 1,2-dichloroethane (25 ml) was added sodium triacetoxyborohydride (0.35 g, 1.57 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous sodium hydrogencarbonate (2×30 ml) and dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue (0.56 g) was purified on column chromatography using a mixture of ethyl acetate/heptane (1:1) as eluent followed by a mixture of 10% triethylamine in ethyl acetate/heptane (1:1) as eluent. Semi pure fractions were collected and the solvent evaporated in vacuo. The residue (180 mg) was subjected to preparative TLC using a mixture of 10% triethylamine in ethyl acetate/ethanol (4:1) as eluent. The desired band was taken off and extracted with methanol (400 ml) for 0.5 hour, filtered and the solvent evaporated in vacuo, which afforded 250 mg (>100%, contains dichloromethane and silicagel) of 5-(((benzo[1,3]dioxol-5-ylmethyl)-amino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
LC-MS: Rt=5.75 min, m/z: 547 [M+H]+.
5-(((Benzo[1,3]dioxol-5-ylmethyl)-amino)methyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (250 mg) was dissolved in dichloromethane (9 ml) and trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred 16 hours at room temperature. The volatiles were evaporated in vacuo and the residue trituated with a small portion of diethyl ether. The solid precipitate was filtered off and washed with diethyl ether and dried in vacuo at 50° C. for 16 hours, which afforded 160 mg of the title compound as a solid.
Calculated for C19H18N2O8S, 2×TFA, 3×H2O; C, 38.56%; H, 3.66%; N, 3.91%. Found: C, 38.61%; H, 3.90%; N, 4.22%.
Example 68




5-((2-Methoxy-benzylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 66 using 2-(tert-butoxyoxalyl-amino)-5-formyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-methoxy-benzylamine as starting material.
Calculated for C19H20N2O7S, 0.75×TFA; C, 48.67%; H, 4.13%; N, 5.54%. Found: C, 48.61%; H, 4.42%; N, 5.35%.
Example 69




5-((2-Benzo[3,1]dioxol-5-yl-acetylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 3,4-methylenedioxy phenylacetic acid (0.22 g, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (0.27 g, 1.42 mmol) in acetonitrile (6 ml) was added triethylamine (0.46 ml, 3.27 mmol). The resultant mixture was allowed to stir at ambient temperature for 10 min. before 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.311 g, 1.09 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for 18 hours and then concentrated in vacuo. To the residue ethyl acetate and water were added and the layers separated. The organic layer was washed with hydrochloric acid (0.5M, (v/v)), saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was used immediately in the next step.
1H-NMR (CDCl3) δ 6.78–6.69 (m, 3H), 5.97 (bs, 2H), 5.95 (s, 2H), 4.60–4.58 (m, 1H), 4.53 (s, 2H), 3.73 (ddd, 1H, J=14 Hz, J=7.6 Hz and J=3.2 Hz), 3.65–3.59 (m, 1H), 3.49 (s, 2H), 3.11 (ddd, 1H, J=12.4 Hz, J=4 Hz and J=4.4 Hz), 2.76 (dm, 1H), 2.44 (ddt, 1H, J=19.6 Hz, J=13.2 Hz and J=2.4 Hz), 1.51 (s, 9H).
To a solution of the above crude 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.17 g, 0.38 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.22 g, 1.14 mmol). The reaction mixture was stirred at room temperature for 18 hours, the volatiles evaporated in vacuo and the residue diluted with ethyl acetate. The organic layer was washed with hydrochloric acid (1% (v/v), 2×25 ml), saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered, concentrated in vacuo and the residue subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:2) as eluent, which afforded 0.12 g (55%) of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.51 (bs, 1H), 6.78 (d, 1H, J=8 Hz), 6.77 (d, 1H, J=1.6 Hz), 6.71 (dd, 1H, J=8.4 Hz and J=1.6 Hz), 5.96 (s, 2H), 4.70 (m, 2H, J=35 Hz, J=15.2 Hz, J=14.4 Hz and J=2 Hz), 3.77 (ddd, 1H, J=10.8 Hz, J=7.6 Hz and J=3.2 Hz), 3.67–3.62 (m, 1H), 3.50 (s, 2H), 3.15 (ddd, 1H, J=12.8 Hz, J=8.4 Hz and J=4.4 Hz), 2.87 (dt, 1H, J=16 Hz and J=3 Hz), 2.57–2.50 (m, 1H), 1.61 (s, 9H), 1.57 (s, 9H);
LC-MS: m/z: 575.0 [M+H]+
2-(tert-Butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.12 g, 0.20 mmol) was dissolved in a 50% solution of trifluoroacetic acid/dichloromethane (2 ml). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo to 1⁄5 of the volume and the precipitate filtered off and washed with dichloromethane (2×) affording 50 mg (50%) of the title compound as a solid.
1H-NMR (DMSO-d6) δ 12.32 (bs, 1H), 8.20 (t, 1H, J=6.8 Hz), 6.81 (m, 2H), 6.70 (m, 1H), 5.95 (s, 2H), 4.80 (d, 1H, J=19.6 Hz), 4.63 (d, 1H, J=20 Hz), 3.65 (m, 1H), 3.34 (s, 2H), 3.30–3.20 (m, 3H), 2.87 (dm, 1H);
LC-MS: m/z: 463.0 [M+H]+.
Example 70




5-(((5-Methoxy-2-methyl-1H-indol-3-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
To a solution of 5-methoxy-2-methyl indole-3-acetic acid (0.26 g, 1.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (0.27 g, 1.4 mmol) in acetonitrile (10 ml) was added triethylamine (0.46 ml, 3.2 mmol). The reaction mixture was allowed to stir for 10 min at room temperature before compound 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.307 g, 1.08 mmol) was added. The reaction mixture was allowed to stir for 18 hours and then concentrated in vacuo. Ethyl acetate and water were added and the layers separated. The organic layer was washed with hydrochloric acid (0.5M, (v/v)), saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was 5-(((5-methoxy-2-methyl-1H-indol-3-carbonyl)amino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was used immediately in the next step.
1H-NMR (CDCl3) δ 7.90 (bs, 1H), 7.19 (d, 1H, J=8.8 Hz), 6.87 (d, 1H, J=2.4 Hz), 6.79 (dd, 1H, J=8.8 Hz and J=2.4 Hz), 6.18 (m, 1H), 5.94 (s, 2H), 4.33 (m, 2H, J=25 Hz, J=14 Hz, J=2.8 Hz and J=1.6 Hz), 3.80 (s, 3H), 3.76 (ddd, 1H, J=14 Hz, J=8 Hz and J=2.8 Hz), 3.65 (s, 3H), 3.53 (m, 1H), 2.99 (ddd, 1H, J=13 Hz, J=5.6 Hz and J=4 Hz), 2.76 (dt, 1H, J=16.8 Hz, J=2.8 Hz), 2.42–2.40 (m, 1H), 2.38 (s, 3H), 1.51 (s, 9H).
To a solution of the crude 2-amino-5-(((5-methoxy-2-methyl-1H-indol-3-carbonyl)amino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.35 g, 0.72 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.42 g, 2.1 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue diluted with ethyl acetate. The organic layer was washed with hydrochloric acid (1% (v/v), 2×25 ml), saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered, concentrated in vacuo and the residue subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:1) as eluent, which afforded 0.24 (55%) of 2-(tert-butoxyoxalyl-amino)-5-(((5-methoxy-2-methyl-1H-indol-3-carbonyl)amino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.50 (bs, 1H), 7.92 (s, 1H), 7.20 (dd, 1H, J=8.4 Hz and J=0.4 Hz), 6.88 (d, 1H, J=2.4 Hz), 6.80 (dd, 1H, J=8.8 Hz and J=2.4 Hz), 6.21 (m, 1H), 4.56 (dd, 1H, J=14.8 Hz and J=2.8 Hz), 4.44 (dt, 1H, J=14.4 Hz and J=2.8 Hz), 4.11 (q, 1H, J=7.2 Hz), 3.81–3.75 (m, 1H), 3.79 (s, 3H), 3.66 (s, 2H), 3.58–3.54 (m, 1H), 3.01 (ddd, 1H, J=14 Hz, J=8.8 Hz and J=4.4 Hz), 2.85 (dt, 1H, J=16.8 Hz and J=6 Hz), 2.52–2.45 (m, 1H), 2.38 (s, 3H), 1.60 (s, 9H), 1.57 (s, 9H);
LC-MS: m/z: 614.1 [M+H]+.
2-(tert-Butoxyoxalyl-amino)-5-(((5-methoxy-2-methyl-1H-indol-3-carbonyl)amino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.24 g, 0.39 mmol) was dissolved in a 50% solution of trifluoroacetic acid/dichloromethane (2 ml). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo to 1⁄5 of the volume and the precipitate filtered off. The filtrate was washed with dichloromethane (2×) and dried, which afforded 100 mg (50%) of the title compound as a solid.
1H-NMR (DMSO-d6) δ 12.31 (bs, 1H), 10.58 (s, 1H), 7.98 (t, 1H, J=6.8 Hz), 7.08 (d, 1H, J=11.2 Hz), 6.98 (d, 1H, J=2.4 Hz), 6.58 (dd, 1H, J=11.6 Hz and J=2.8 Hz), 5.75 (d, 1H, J=0.8 Hz), 4.77 (d, 1H, J=19.6 Hz), 4.58 (d, 1H, J=20 Hz), 3.69 (s, 3H), 3.64–3.62 (m, 1H), 3.43 (s, 2H), 3.31–3.20 (m, 1H), 2.92–2.84 (m, 1H), 2.52 (m, 1H—partially obscured by DMSO), 2.30 (s, 3H);
LC-MS: m/z: 500.1 [M−H]−.
Example 71




5-(1,3-Dioxo-5-propylcarbamoyl-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
In a 10-mL scintillating vial, a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (149 mg, 0.5 mmol) in N,N-dimethylformamide (4 mL) was treated with trimellitic anhydride, (120 mg, 0.62 mmol) and stirred at 100° C. for 24 hours. The solution was then diluted with ethyl acetate (25 ml) and washed with 0.5N aqueous hydrogen chloride (25 mL) and brine (25 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo affording 229 mg (100%) of 2-(2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid as a solid.
1H-NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.49 (d, 1H, J=9 Hz), 8.00 (d, 1H, J=10 Hz), 4.64–4.54 (m, 2H), 4.08–4.02 (m, 2H), 3.88–3.80 (m, 1H), 2.98–2.83 (m, 1H), 2.68–2.54 (m, 1H), 1.57 (s, 9H).
HPLC (254.4 nm) Rt=3.98 min.
In a 250 mL round bottom flask, a solution of 2-(2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (500 mg, 1.1 mmol) in dichloromethane (7 mL) was treated with a solution of imidazol-1-yl-oxo-acetic acid tert-butyl ester (633 mg, 3.2 mmol) in dichloromethane (1.0 mL). After stirring for 4 hours at room temperature the reaction solution was dissolved in ethyl acetate (100 mL) and washed with distilled water (2×50 mL), 0.5 N aqueous hydrogen chloride (3×50 mL), and brine (50 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to yield 370 mg (58%) of 2-(2-(tert-butoxyoxalyl-amino)-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid as a solid.
1H-NMR (300 MHz, CDCl3) δ12.49 (s, 1H), 8.58 (s, 1H), 8.50 (d, 1H, J=8 Hz), 8.00 (d, 1H, J=8 Hz), 4.84–4.65 (m, 2H), 4.17–4.00 (m, 2H), 3.92–3.84 (m, 1H), 3.08–2.94 (m, 1H), 2.78–2.64 (m, 1H), 1.61 (s, 9H), 1.57 (s, 9H).
In a 50 mL round bottom flask, a solution of 2-(2-(tert-butoxyoxalyl-amino)-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (208 mg, 0.36 mmol) in dichloromethane (5.0 mL) was treated with N,N-diisopropyl ethylamine (200 μL, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol). The solution was allowed to stir for 50 minutes at room temperature before propylamine (30 μL, 0.36 mmol) was added dropwise. The solution was stirred for an additional 18 hours at room temperature. The volatiles were evaporated in vacuo and the residue was purified by silica gel chromatography using a mixture of hexane/ethyl acetate (9:1) as eluent, which afforded 51 mg (23%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-5-propylcarbamoyl-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (300 MHz, CDCl3) δ 12.48 (s, 1H), 8.24–8.16 (m, 2H), 7.93 (d, 1H, J=8 Hz), 6.39 (t, 1H, J=6 Hz), 4.18–4.63 (m, 2H), 4.10–3.96 (m, 2H), 3.92–3.78 (m, 1H), 3.47 (q, 2H, J=7 Hz), 2.99 (d, 1H, J=17), 2.76–2.60 (m, 1H), 1.68 (q, 2H, J=7 Hz), 1.61 (s, 9H), 1.57 (s, 9H), 1.01 (t, 3H, J=7 Hz).
In a 25 mL round bottom flask 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-5-propylcarbamoyl-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (4 mL). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 32 mg (90%) of the title compound as a solid.
1H-NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 8.00 (s, 1H), 4.90–4.48 (m partially obscured by water, 2H), 4.00–3.64 (m partially obscured by water, 3H), 3.36–3.16 (m partially obscured by water, 2H), 3.13–2.90 (d partially obscured by water 1H), 2.69–2.53 (m partially obscured by DMSO, 1H), 1.69–1.38 (m, 2H), 1.00–0.74 (m, 3H).
HPLC (254.4 nm) Rt=3.09 min.
MS (APCI−) m/z: 515.4 [M−H]−.
Example 72




7-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
2-(tert-Butoxyoxalyl-amino)-7-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (50 mg, 0.067 mmol) was dissolved in a mixture of ethyl acetate/ethanol (3 mL, 1:1). Palladium on activated carbon (10%, 10 mg) was added and the solution degassed and stirred under hydrogen (1 atm) for 72 hours. The mixture was filtered through celite and the filter cake washed with hot ethyl acetate. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (10% ethyl acetate/dichloromethane) to obtain 42 mg (95%) of 2-(tert-butoxyoxalyl-amino)-7-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as an oil.
1H-NMR (400 MHz, CDCl3) δ 12.59–12.53 (2s, 1H), 7.64–7.53 (m, 1H), 7.42–7.36 (m, 1H), 7.19–7.11 (m, 1H), 5.58–5.37 (m, 1H), 4.37–4.00 (m, 2H), 3.86–3.78 (m, 1H), 3.32–3.18 (m, 1H), 2.99–2.94 (m, 1H), 2.84–2.69 (m, 1H), 1.62–1.59 (3s, 18H), 1.17–1.11 (2s, 9H);
LC-MS: Rt=4.55 min, m/z: 658 [M+H]+,
2-(tert-Butoxyoxalyl-amino)-7-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (42 mg, 0.064 mmol) was dissolved in a solution of 50% trifluoroacetic acid/methylene chloride (3 mL). The reaction was stirred at ambient temperature for 7 hours, concentrated in vacuo and evaporated from dichloromethane (10 ml) three times. The resulting precipitate was washed with dichloromethane and dried in vacuo to give 29 mg (81%) of the title compound as a solid trifluoroacetate.
1H-NMR (400 MHz, DMSO-d6) δ 12.32 (bs, 1H), 11.26 (s, 1H), 9.30 (bs, 2H), 7.64 (t, 1H, J=7 Hz), 7.33 (d, 1H, J=7 Hz), 7.25 (d, 1H, J=7 Hz), 4.84 (s, 1H), 4.06–3.96 (m, 2H), 3.56 (m, 2H), 3.05 (bs, 2H),
LC-MS: Rt=1.26 min, m/z: [M+H]+,
Example 73




5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0° C. in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4×40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87%) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid.
1H-NMR (300 MHz, CDCl3): δ 7.43 (d, 1H, J=9 Hz), 7.12 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 5.05 (bs, 1H), 3.90 (s, 3H), 2.47 (s, 3H).
To a solution of the above methyl ester (256 mg, 1.54 mmol) and N,N-diisopropylethylamine (530 μl, 3.0 mmol) in dichloromethane (8 ml) at 0° C. methyloxymethyl chloride (175 μl, 2.3 mmol) was added dropwise. The solution was allowed slowly to warm to room temperature and stired for 24 hours. The solution was diluted with dichloromethane (12 ml), washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (4:1) as eluent, which afforded 269 mg (85%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.
1H-NMR (300 MHz, CDCl3): δ 7.48 (d, 1H, J=8 Hz), 7.24–7.15 (m, 2H), 5.22 (s, 2H), 3.90 (s, 3H), 3.50 (s, 3H), 2.47 (s, 3H).
In a 25 ml round-bottom flask, N-bromosuccinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.
1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, 1H, J=6, 3 Hz), 7.29 (d, 2H, J=3 Hz), 5.27 (s, 2H), 5.05 (s, 2H), 3.91 (s, 3H), 3.50 (s, 3H).
In a 100 ml round-bottom flask, 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (298 mg, 0.74 mmol) and N,N-diisopropylethylamine (195 μl, 1.12 mmol) were dissolved in acetonitrile (40 ml). 2-Bromomethyl-3-methoxymethoxy-benzoic acid methyl ester (193 mg, 0.67 mmol) in acetonitrile (5 ml) was slowly added to the amine solution via gastight syringe over 24 hours, followed by stirring at room temperature for an additional 36 hours. The solution was concentrated in vacuo, the residue redissolved in ethyl acetate (25 ml), and washed with saturated aqueous sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 345 mg (81%) of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (300 MHz, CDCl3): δ 7.67 (d, 1H, J=8 Hz), 7.57–7.38 (m, 5H), 7.14 (d, 2H, J=8 Hz), 6.96 (m, 2H), 6.77 (d, 2H, J=9 Hz), 6.20 (d, 2H, J=6 Hz), 5.96 (s, 2H), 4.69–2.58 (m, 17H), 1.55 (s, 9H).
In a 50, ml round-bottom flask a solution of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (338 mg, 0.58 mmol) in dichloromethane (20 ml) was treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (575 mg, 2.9 mmol). After stirring for 18 hours at room temperature, the mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 310 mg (75%) of 2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (300 MHz, CDCl3): δ 12.57 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.43 (t, 1H, J=8 Hz), 7.26 (d, 1H, J=8 Hz), 7.13 (d, 2H, J=9 Hz), 6.78 (d, 2H, J=9 Hz), 5.28 (s, 2H), 4.47 (q, 2H, J=18 Hz), 4.02–3.44 (m, 11H), 2.97 (dd, 1H, J=18 Hz and J=5 Hz), 2.76 (dd, 1H, J=17 Hz and J=5 Hz), 1.63 (s, 9H), 1.59 (s, 9H).
10% Pd/C (145 mg, 50% by weight) was added to a mixture of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (283 mg, 0.40 mmol) in 10% formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50% by weight) was added to the reaction mixture. After stirring at room temperature for an additional 20 hours, the catalyst was removed via fitration through celite. Fresh Pd/C (255 mg) and ammonium formate (1.0 g) were added to the residue (253 mg, 0.36 mmol) dissolved in 10% formic acid in methanol (10 ml). The solution was heated to 40° C. for 48 hours. Catalyst was removed via filtration through celite and liberal washing with methanol. Purification by chromatotron (ethyl acetate/triethylamine (99:1)) afforded 63 mg (27%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A and 46 mg (19%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester B.
A: 1H-NMR (300 MHz, CDCl3): δ 12.54 (s, 1H), 7.50 (d, 1H, J=8 Hz), 7.41 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 5.27 (s, 2H), 4.52 (dd, 2H, J=30 Hz and J=19 Hz), 4.08–3.90 (m, 2H), 3.86–3.67 (m, 2H), 3.51 (s, 3H), 3.27 (m, 1H), 2.99 (dd, 1H, J=18 Hz and J=4 Hz), 2.53 (dd, 1H, J=18. Hz and J=11 Hz), 1.61 (s, 9H), 1.53 (s, 9H).
LC-MS (APCI+) m/z: 588 [M+H]+; Rt=1.32 min.
B: 1H-NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 7.50 (d, 1H, J=7 Hz), 7.41 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 5.27 (s, 2H), 4.50 (dd, J=28 Hz and J=18 Hz), 3.93–3.68 (m, 4H), 3.51 (s, 1H), 3.51 (s, 3H), 3.31 (m, 1H), 2.88 (dd, 1H, J=18 Hz and J=4 Hz), 2.68 (dd, 1H, J=19 Hz and J=9 Hz), 2.46 (s, 3H), 1.61 (s, 9H), 1.54 (s, 9H).
LC-MS (APCI+) m/z: 602 [M+H]+; Rt=1.35 min.
2-(tert-Butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A (63 mg, 0.11 mmol) was dissolved in 30% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 57 mg (90%) of the title compound as a solid trifluoroacetate.
1H-NMR (300 MHz, DMSO-d6): δ 12.30 (s, 1H), 10.17 (s, 1H), 9.23 (s, 2H, J=5 Hz and J=7 Hz), 7.34 (t, 1H, J=6 Hz), 7.19 (d, 1H, J=5 Hz), 7.03 (d, 1H, J=6 Hz), 5.76 (s, 2H), 4.53 (d, 1H, J=13 Hz), 4.43–4.22 (m, 3H), 4.07 (m, 1H), 3.91 (m, 1H), 3.70 (m, 1H), 3.10 (m, 1H), 2.82 (dd, 1H, J=14 Hz and J=8 Hz).
Example 74




5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The above 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester B (46 mg; 0.08 mmol) was dissolved in 30% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 41 mg (90%) of the title compound as a solid trifluoroacetate.
1H-NMR (400 MHz, CDCl3): δ 12.39 (s, 1H), 10.19 (s, 1H), 10.10 (s, 1H), 7.32 (t, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.2 Hz), 7.02 (t, 1H, J=7.2 Hz), 4.55 (d, 2H, J=15 Hz), 4.0–4.5 (m, 4H), 2.95–3.70 (m, 5H), 2.85 (s, 3H).
LC-MS (APCI+) m/z: 446 [M+H]+; Rt=1.02 min.
Example 75




5-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
Saccharin (8.8 g, 48 mmol) and phosphorous pentachloride (15 g, 72 mmol) were added neat to a round bottom flask equipped with a short path distillation column. The mixture was heated to 175° C. After approximately 0.5 hour, phosphorous oxychloride slowly distilled off. Upon completion of the reaction, the mixture was cooled and the resultant solid recrystallized from benzene affording 3.6 g (37%) of 3-chloro-benzo[d]isothiazole 1,1-dioxide as a solid.
1H-NMR (CDCl3): δ 7.92 (d, 1H, J=6.9 Hz), 7.8 (m, 3H).
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (155 mg, 0.384 mmol) and triethylamine (59 μl, 0.423 mmol) in dichloromethane (2 ml) at 0° C., was added a solution of 3-chloro-benzo[d]isothiazole 1,1-dioxide (85.2 mg, 0.423 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was judged complete by tlc (dichloromethane/ethyl acetate (1:1)). The reaction mixture was washed with water (3×20 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude residue was subjected to flash chromatography using a gradient from 100% dichloromethane to dichloromethane/ethyl acetate (80/20) as eluent, which afforded 200 mg (92%) of 2-amino-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a foam.
1H-NMR (CD3OD): δ 7.99 (m, 1H), 7.87 (m, 1H), 7.79 (m, 2H), 7.19 (d, 2H, J=8.4 Hz), 6.75 (d, 2H, J=8.7 Hz), 3.88–3.79 (m, 2H), 3.75–3.59 (m, 3H), 3.69 (s, 3H), 3.52–3.46 (m, 2H), 2.84 (dd, 1H, J=15.3 Hz and J=5.4 Hz), 2.68 (dd, J=18 Hz and J=4.5 Hz), 1.46 (s, 9H).
LC-MS: Rt=2.83, m/z: 569 [M+H]+
To a solution of 2-amino-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (129 mg, 0.227 mmol) in tetrahydrofuran (3 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (1.1 ml, 1.1 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue subjected to flash chromtography using a mixture of ethyl acetate/dichloromethane (10:90) as eluent, which afforded 142 mg (90%) of 2-(tert-butoxyoxalyl-amino)-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3): δ 7.92 (d, 1H, J=6.3 Hz), 7.73 (m, 2H), 7.56 (d, 1H, J=5.7 Hz), 7.20 (d, 2H, J=6.3 Hz), 7.05 (bs, 1H), 6.87 (d, 2H, J=6.6 Hz), 3.91 (m, 2H), 3.82–3.72 (m, 2H), 3.79 (s, 3H), 3.61–3.49 (m, 2H), 3.44 (m, 1H), 3.11 (dd, 1H, J=15 Hz and J=3.6 Hz), 2.72 (dd, 1H, J=12 Hz and J=4.2 Hz), 1.63 (s, 18H);
LC-MS: Rt=3.48, m/z: 697 [M+H]+
2-(tert-Butoxyoxalyl-amino)-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (120 mg, 0.172 mmol) was dissolved in a mixture of ethanol (4 ml) and formic acid (0.5 ml). 10% Pd—C (20 mg) was added and the reaction mixture stirred at ambient temperature for 4 days (after the second day, 150 mg of additional 10% Pd—C was added). The reaction mixture was filtered through celite and the celite washed with dichloromethane. The organic fractions were combined and concentrated in vacuo. The resultant oil was subjected to preparative thin layer chromatography (dichloromethane/methanol (95:5)), which afforded 17 mg (17%) of 2-(tert-butoxyoxalyl-amino)-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 7.91 (m, 1H), 7.72 (m, 3H), 7.34 (bs, 1H), 4.16–4.08 (m, 1H), 4.07 (dd, 2H, J=36.3 Hz and J=8.7 Hz), 3.38–3.30 (m, 1H), 3.22–3.06 (m, 2H), 2.51 (dd, 1H, J=16.8 Hz and J=9.9 Hz), 1.61 (s, 18H).
2-(tert-Butoxyoxalyl-amino)-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (15 mg, 0.026 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (3 ml). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo and re-evaporated from acetonitrile (2×). The residue was washed with dichloromethane and dried in vacuo to give 16 mg (90%) of the title compound as a solid trifluoroacetate.
1H—NMR (CD3OD): δ 7.98 (d, 1H, 7.2 Hz), 7.92 (d, 1H, J=6.6 Hz), 7.83 (m, 2H), 4.51–4.39 (m, 2H), 4.11–4.08 (m, 1H), 3.97–3.91 (m, 2H), 3.53–3.47 (m, 1H), 3.16–3.10 (m, 1H).
Example 76




7-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
3-Chloro-benzo[d]isothiazole-1,1-dioxide (160 mg, 0.79 mmol) and diisopropylethylamine (1501 μl, 0.86 mmol) were dissolved in dichloromethane (7 ml) at 0° C. 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (284 mg, 0.70 mmol) was added and the mixture was stirred for 15 minutes at 0° C., diluted with dichloromethane, (10 ml) and washed with water (20 ml) and brine (20 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of hexanes/ethyl acetate (1:1) to pure ethyl acetate as eluent, which afforded 309 mg (77%) of 2-amino-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an foam.
1H-NMR (300 MHz, CDCl3): δ 7.89 (d, 1H, J=8 Hz), 7.77–7.63 (m, 2H), 7.37 (d, 1H, J=7 Hz), 7.25 (d, 2H, J=10 Hz), 6.82 (d, 2H, J=8 Hz), 6.62 (bs, 1H), 6.08 (s, 2H), 3.91 (m, 1H), 3.71 (s, 3H), 3.49–2.65 (m, 8H), 1.59 (s, 9H).
LC-MS (APCI+) m/z: 569 [M+H]+, [M+Na] 591; Rt=2.85 min.
2-Amino-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (102 mg, 0.18 mmol) in dichloromethane (10 ml) was treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (85 mg, 0.43 mmol). After stirring for 18 hours at room temperature, the reaction solution was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a gradient of hexanes/ethyl acetate (1:1) to pure ethyl acetate as gradient, which afforded 98 mg (78%) of 2-(tert-butoxyoxalyl-amino)-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (300 MHz, CDCl3): δ 12.57 (s, 1H), 7.89 (d, 1H, J=8 Hz), 7.77–7.63 (m, 2H), 7.39 (d, 1H, J=7 Hz), 7.25 (d, 2H, J=9 Hz), 6.84 (d, 2H, J=9 Hz), 6.64 (bs, 1H), 3.99–2.76 (m, 12H), 1.64 (s, 9H), 1.63 (s, 9H). 10% Pd/C (100 mg) was added to a mixture of 2-(tert-butoxyoxalyl-amino)-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (98 mg, 0.14 mmol) in 10% formic acid in methanol (10 ml). After stirring at room temperature for 48 hours, the catalyst was removed via filtration through celite and liberal washing with methanol. The volatiles were removed in vacuo and the residue purified by chromatotron (ethyl acetate/triethylamine, 99:1), which afforded 32 mg (40%) of 2-(tert-butoxyoxalyl-amino)-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (300 MHz, CDCl3): δ 12.48 (s, 1H), 10.21–9.15 (m, 2H), 8.49–7.42 (m, 3H), 5.62–5.00 (bs, 1H), 4.53–2.87 (m, 8H), 1.61 (s, 18H).
HPLC (254.4 nm) Rt=3.67 minutes.
2-(tert-Butoxyoxalyl-amino)-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (32 mg) was dissolved in a mixture of 30% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 29 mg (90%) of the title compound as a solid trifluoroacetate.
1H-NMR (300 MHz, DMSO-d6): δ 12.36 (s, 1H), 9.92 (bs, 1H), 9.73 (bs, 1H), 9.38 (bs, 1H), 8.20 (m, 1H), 8.05 (m, 1H), 7.89 (m, 2H), 4.95 (s, 1H), 4.12–3.00 (m partially obscured by water, 8H).
LC-MS (APCI+) m/z: 466 [M+H]+; Rt=0.66 min.
Example 77




5-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
2-Methoxy-6-methylbenzoic acid ethyl ester (500 mg, 2.67 mmol), N-bromosuccinimide (483.8 mg, 2.72 mmol) and 2,2′-azobis(2-methyl-propionitrile) (30.2 mg, 0.123 mmol) in carbon tetrachloride (10 ml) were heated to reflux. After 18 hours, the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane (100 ml) and washed with water (2×50 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (702 mg) was purified by column chromatography using a mixture of hexanes/dichloromethane (1:1) as eluent, which afforded 573 mg (85%) of 6-bromomethyl-2-methoxy-benzoic acid ethyl ester as an oil.
1H-NMR (CDCl3): δ7.37 (t, 1H, J=8.4 Hz), 7.01 (d, 1H, J=8.1 Hz), 6.90 (d, 1H, J=8.4 Hz), 4.54 (s, 2H), 4.45 (q, 2H, J=7.2 Hz), 3.82 (s, 3H), 1.42 (t, 3H, J=9 Hz).
6-Bromomethyl-2-methoxy-benzoic acid ethyl ester (71.1 mg, 0.260 mmol) dissolved in acetonitrile (5 ml) and diisopropylethylamine (453 μl, 2.60 mmol) was stirred at room temperature. To this mixture 2-amino-5-amino-methyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (200 mg, 0.52 mmol) dissolved in acetonitrile (5 ml) was added syringe pump (0.2 ml/min.). Once addition was complete, the reaction mixture was allowed to stir for 2 hours. The reaction mixture was concentrated in vacuo, and the residue diluted with ethylacetate (50 ml). The organic layer was washed with saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue (308 mg) was subjected to column chromatography using a gradient of hexane/ethyl acetate (95:5) to (50:50) and then dichloromethane/ethyl acetate (95:5) as eluents, which afforded 106 mg (75%) of 2-amino-6-(4-methoxy-benzyl)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3): δ 7.48 (t, 1H, J=7.5 Hz), 7.12 (d, 2H, J=8.4 Hz), 7.01 (d, 1H, J=7.5 Hz), 6.91 (d, 1H, J=8.4 Hz), 6.76 (d, 2H, J=7.8 Hz), 5.95 (bs, 2H), 4.37 (s, 2H), 4.05 (m, 1H), 3.97 (s, 3H), 3.88–3.78 (m, 2H), 3.81 (s, 3H), 3.71–3.39 (m, 4H), 2.90 (dd, 1H, J=18 Hz and J=5.4 Hz), 2.62 (dd, 1H, J=18 Hz and J=5.4 Hz), 1.53 (s, 9H).
To a solution of 2-amino-6-(4-methoxy-benzyl)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (105 mg, 0.192 mmol) in tetrahydrofuran (3 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.534 ml, 0.534 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture concentrated in vacuo and the residue subjected to flash chromtography using a mixture of ethyl acetate/dichloromethane (10:90) as eluent, which afforded 85 mg (66%) of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3): δ 7.47 (t, 1H, J=5.7 Hz), 7.10 (d, 2H, J=6 Hz), 6.99 (d, 1H, J=5.7 Hz), 6.90 (d, 1H, J=6.3 Hz), 6.76 (d, 2H, J=6.3 Hz), 4.37 (q, 2H, J=11.4 Hz), 3.99–3.92 (m, 1H), 3.97 (s, 3H), 3.79–3.76 (m, 2H), 3.77 (s, 3H), 3.66 (d, 1H, J=12.6 Hz), 3.58–3.50 (m, 3H), 2.95 (dd, 1H, J=13.5 Hz and J=3.6 Hz), 2.70 (dd, 1H, J=13.5 Hz and J=3.6 Hz), 1.61 (d, 9H), 1.57 (s, 9H).
2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (66 mg, 0.12 mmol) was dissolved in ethanol (2 ml) and formic acid (0.3 ml). 10% Pd—C (15 mg) was added and the reaction mixture stirred at room temperature for 3 days. TLC (hexane/ethyl acetate (1/1)) indicated reaction complete. The reaction mixture was filtered through celite and the celite washed with dichloromethane. The organic fractions were combined and subjected to preparative thin layer chromatography (hexane/ethyl acetate (1/1) to yield 14.7 mg (22%) of 2-(tert-butoxyoxalyl-amino)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3): δ 7.48 (t, 1H, J=7.5 Hz), 7.01 (d, 1H, J=7.2 Hz), 6.90 (d, 1H, J=8.4 Hz), 5.50 (d, 2H, J=6.6 Hz), 4.04–3.90 (m, 1H), 3.97 (s, 3H), 3.24 (m, 1H), 3.01–2.95 (m, 1H), 2.57–2.43 (m, 2H), 1.62 (s, 9H), 1.57 (s, 9H).
2-(tert-Butoxyoxalyl-amino)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (14.7 mg, 0.026 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (2 ml). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo and re-evaporated from acetonitrile (2×). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 13 mg (89%) of the title compound as a solid trifluoroacetate.
1H-NMR (CD3OD): δ 7.56 (t, 1H, J=8.1 Hz), 7.13 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=8.1 Hz), 4.87–4.44 (m, 4H), 4.15 (m, 1H), 3.90 (s, 3H), 3.88–3.79 (m, 1H), 3.43 (m, 1H), 2.98 (m, 2H);
LC-MS: Rt=0.71, m/z: 446 [M+H]+.
Example 78




5-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-hydroxy-6-methyl-benzoic acid ethyl ester (5.00 g, 27.8 mmol) and t-butyl-di-methylsilyl chloride (6.27 g, 41.6 mmol) in dichloromethane (100 ml) was added diisopropyl ethylamine. The solution was stirred at 50° C. for 24 hours, washed with water, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo, which afforded 7.6 g (93%) of 2-(tert-butyl-dimethyl-silanyloxy)-6-methyl-benzoic acid ethyl ester as an oil.
1H-NMR (CDCl3): δ 7.13 (t, 1H, J=7.5 Hz), 6.78 (d, 1H, J=7.5 Hz), 6.67 (d, 1H, J=7.5 Hz), 4.35 (q, 2H, J=7.2 Hz), 2.29 (s, 3H), 1.38 (t, 3H, J=7.2 Hz), 0.97 (s, 9H), 0.23 (s, 6H).
2-(tert-Butyl-dimethyl-silanyloxy)-6-methyl-benzoic acid ethyl ester (7.6 g, 25.8 mmol), N-bromosuccinimide (4.82 g, 27.1 mmol) and azobis(cyclohexanecarbonitrile) (0.32 g, 13 mmol) were dissolved in tetrachlormethane (130 ml). The solution was stirred at room temperature for 60 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel column using a gradient of 1–2% ethyl acetate/hexane as eluent, which afforded 8.0 g (83%) of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester as an oil.
1H-NMR (CDCl3): δ 7.21 (t, 1H, J=8.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=8.4 Hz), 4.51 (s, 2H), 4.40 (q, 2H, J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz), 0.98 (s, 9H), 0.23 (s, 6H).
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (3.00 g, 7.45 mmol) and diisopropyl ethylamine (1.93 ml, 11.2 mmol) in acetonitrile at room temperature was added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (2.78 g, 7.45 mmol) in acetonitril over 48 hours. The solution was stirred for 12 hours after the addition was complete. The volatiles were evaporated in vacuo and the residue was taken into ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with a mixture of 20% ethyl acetate/Hexane, which afforded 3.2 g (66. %) of 2-amino-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl]-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3): δ 7.36 (t, 1H, J=8.0 Hz), 7.11 (d, 2H, J=8.8 Hz), 6.99 (d, 1H, J=8.0 Hz), 6.82 (d, 1H, J=8.0 Hz), 6.76 (d, 2H, J=8.8 Hz), 5.94 (s, 2H), 4.48 (d, 1H, J=16.8 Hz), 4.33 (d, 1H, J=16.8 Hz), 3.90–3.45 (m, 7H), 3.78 (s, 3H), 2.95 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 2.72 (dd, 1H, J=17 Hz and J=5.6 Hz), 1.52 (s, 9H), 1.05 (s, 9H), 0.26 (s, 6H).
To a stirred solution of 2-amino-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (2.37 g, 3.64 mmol) in tetrahydrofuran (50 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (2.14 mg, 10.9 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was taken into ethyl acetate (100 ml). The solution was washed with 0.5 N hydrochloric acid solution (2×20 ml), saturated sodium bicarbonate (2×20 ml) and brine (20 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed using a gradient of 10–20% ethyl acetate/Hexane as eluent, which afforded 2.40 g (92%) of 2-(tert-butoxyoxalyl-amino)-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.59 (s, 1H), 7.37 (t, 1H, J=8.0 Hz), 7.10 (d, 2H, J=8.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.77 (d, 2H, J=8.8 Hz), 4.50 (d, 1H, J=16.8 Hz), 4.34 (d, 1H, J=16.8 Hz), 3.90–3.45 (m, 7H), 3.77 (s, 3H), 2.95 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 2.72 (dd, 1H, J=18 and J=5.6 Hz), 1.61 (s, 9H), 1.58 (s, 9H), 1.06 (s, 9H), 0.26 (s, 6H).
To a solution of 2-(tert-butoxyoxalyl-amino)-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (2.40 g, 3.34 mmol) in 10% formic acid/methanol (50 ml) at room temperature under nitrogen was added 10% Pd/C (1.2 g). The mixture was stirred for 48 hours. The Pd/C was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane (10 ml). The resulting solution was poured into hexane. The precipitate was filtered off and dried in vacuo affording 1.3 g (61%) of 2-(tert-butoxyoxalyl-amino) 5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3): δ 12.45 (s, 1H), 8.05 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 4.50 (d, 1H, J=16.8 Hz), 4.45 (q, 2H, J=17 Hz), 4.05 (q, 2H, J=17 Hz), 3.82 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 3.72 (dd, 1H, J=17 Hz and J=5.6 Hz), 3.40 (s, 1H), 3.08 (d, 1H, J=17 Hz), 2.61 (dd, 1H, J=18 Hz and J=7.2 Hz), 1.61 (s, 9H), 1.54 (s, 9H), 1.05 (s, 9H), 0.26 (s, 6H).
To a solution of trifluoroacetic acid (33.3 ml) and H2O (2.7 ml) was added 2-(tert-butoxyoxalyl-amino)-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.70 g, 1.04 mmol). The solution was stirred at room temperature for 40 hours. The solvent was poured into ethyl ether (400 ml). The precipitate was filtered off and dried in vacuo which afforded 450 mg (80%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ12.30 (s, 1H), 9.71 (s, 1H), 9.20 (s, 2H), 7.39 (t, 1H, J=8.0 Hz), 6.99 (d, 1H, J=8.0 Hz), 6.82 (d, 1H, J=8.0 Hz), 4.52 (d, 1H, J=16.8 Hz), 4.36 (d, 2H, J=17 Hz), 4.22 (d, 2H, J=17 Hz), 4.00 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 3.86 (s, 1H), 3.62 (d, 1H, J=17 Hz), 2.81 (dd, 1H; J=18 Hz and J=7.2 Hz);
LC-MS: Rt=1.20 min; m/z=432 [M+H]+
Example 79




5-(7-Benzyloxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-tert-butoxyoxalyl-amino)-5-(7-tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (2.40° g, 3.34 mmol) in 10% formic acid/methanol (50 ml) at room temperature under nitrogen was added 10% Pd/C (1.2 g). The mixture was stirred for 48 hours. The Pd/C was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane (10 ml) and the resulting solution was poured into hexane. The precipitate was filtered off (1.3 g) and the filtrate was evaporated in vacuo. The residual foam (1.1 g) was taken into dichloromethane (50 ml) and treated with di-tert-butyl-dicarbonate (1.1 g, 5.0 mmol) and saturated sodium bicarbonate (20 ml). The mixture was stirred for 2 hours and the organic layer was separated and dried (MgSO4). The solvent was evaporated in vacuo and the residue was chromatographed using a gradient of 10–30% ethyl acetate/Hexane as eluent, which afforded 175 mg of 2-(tert-butoxyoxalyl-amino)-5-(7-hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-carboxylic acid di-tert-butyl ester.
1H-NMR (CDCl3): δ 12.55 (s, 1H), 8.53 (s, 1H), 7.37 (t, 1H, J=7.6 Hz), 6.92 (d, 1H, J=7.6 Hz), 6.83 (d, 1H, J=7.6 Hz), 4.95 (s, 1H), 4.84 (d, 1H, J=16.4 Hz), 4.72 (d, 1H, J=16.0 Hz), 4.56 (d, 1H, J=16.0 Hz), 4.28 (d, 1H, J=17.6 Hz), 4.13 (m, 1H), 3.68 (s, 0.5H), 3.42 (s, 0.5H), 3.16–2.94 (m, 2H), 1.62 (s, 9H), 1.61 (s, 9H), 1.26 (s, 9H).
To a solution of 2-(tert-butoxyoxalyl-amino)-5-(7-hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-carboxylic acid di-tert-butyl ester (16 mg, 0.025 mmol) in N,N-dimethylformamide (0.5 ml) under nitrogen was added sodium hydride (1.0 mg, 0.026 mmol) at room temperature. The solution was stirred for 2 hours and followed by addition of benzyl bromide (5.9 ml, 0.050 mmol). The solution was stirred for 16 hours, diluted with ethyl acetate (20 ml) and washed with 0.5 N hydrochloric acid solution (2×10 ml), saturated sodium bicarbonate (2×10 ml), brine (10 ml), dried (MgSO4), and filtered. The solvent was removed in vacuo. The residue was chromatographed using a gradient of 10–20% ethyl acetate/Hexane as eluent, which afforded 14 mg (76%) of 5-(7-benzyloxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-carboxylic acid di-tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.49 (s, 1H), 7.48 (d, 2H, J=7.2 Hz), 7.35 (m, 3H), 7.28 (d; 1H, J=7.2 Hz), 6.97 (d, 1H, J=7.6 Hz), 6.80 (d, 1H, J=7.6 Hz), 5.32 (s, 2H), 4.97 (m, 2H), 4.82–4.62 (m, 2H), 4.45–4.15 (m, 2H), 3.68 (s, 0.5H), 3.48 (s, 0.5H), 3.16–2.94 (m, 2H), 1.62 (s, 9H), 1.60 (s, 9H), 1.26 (s, 9H).
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (2.7 ml) was added 5-(7-benzyloxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(tert-butoxyoxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-carboxylic acid di-tert-butyl ester (14 mg, 0.019 mmol). The solution was stirred at room temperature for 40 hours. The reaction mixture was poured into ethyl ether (20 ml). The precipitate was filtered off and dried in vacuo affording 8.0 mg (68%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ 12.25 (s, 1H), 9.28 (s, 1H), 9.02 (s, 1H), 7.53 (m, 3H), 7.39 (t, 2H, J=7.6 Hz), 7.13 (d, 1H, J=7.6 Hz), 7.11 (d, 1H, J=8.4 Hz), 5.27 (m, 2H), 4.54 (d, 1H, J=17.2 Hz), 4.38 (d, 2H, J=17.6 Hz), 4.22 (m, 2H), 4.00 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 3.86 (s, 1H), 3.64 (d, 1H, J=17.2 Hz), 2.81 (dd, 1H, J=18 Hz and J=7.2 Hz);
LC-MS: Rt=2.96 min; m/z: 522 [M+H]+
Example 80




5-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was added 2-(tert-butoxyoxalyl-amino)-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (11 mg, 0.014 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was poured into ethyl ether (20 ml). The precipitate was filtered off and dried in vacuo, which afforded 7.0 mg (79%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ 12.39 (s, 1H), 9.95 (s, 1H), 9.75 (s, 2H), 7.42 (t, 1H, J=8.0 Hz), 7.30 (s, 2H), 7.02 (d, 1H, J=7.2 Hz), 6.96 (s, 2H), 6.85 (d, 1H, J=7.2 Hz), 4.95–3.65 (m, 11H), 3.76 (s, 3H).
LC-MS: Rt=1.93 min, m/z: 553 [M+H]+
Example 81




5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a stirred solution of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (15 mg, 0.028 mmol) in tetrahydrofuran (1.0 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (27 mg, 0.11 mmol) in tetrahydrofuran (1.0 ml). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was taken into ethyl acetate (20 ml). The solution was washed with 0.5 N hydrochloric acid solution (2×10 ml), saturated sodium bicarbonate (2×10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo. The residue was chromatographed using a gradient of 10–25% ethyl acetate/hexane as eluent, which afforded 17 mg (93%) of 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.54 (s, 1H), 7.86 (m, 2H), 7.40 (m, 2H), 7.08 (d, 2H J=8.4 Hz), 6.72 (d, 2H, J=8.4 Hz), 4.08 (dd, 1H, J=13.6 Hz and J=8.8 Hz), 3.94 (d, 1H, J=16.8 Hz), 3.82 (d, 1H, J=12.8 Hz), 3.78 (s, 3H), 3.92 (s, 3H), 3.70–3.56 (m, 3H), 3.53 (d, 1H, J=12.8), 2.93 (dd, 1H, J=16.8 Hz and J=4.8 Hz); 2.75 (dd, 1H, J=18.0 Hz and J=5.6 Hz), 1.61 (s, 9H), 1.58 (s, 9H).
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was added 2-(tert-butoxyoxalyl-amino)-5-(1,3-dioxo-1,3-dihydro-isoindol-2 ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (15 mg, 0.023 mmol). The solution was stirred at room temperature for 40 hours. The reaction mixture was poured into ethyl ether (20 ml). The precipitate was filtered off and dried in vacuo, which afforded 13 mg (87%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ 12.38 (s, 1H), 7.89 (d, 4H, J=11.2 Hz), 7.18 (s, 2H), 6.85 (s, 2H), 4.20–3.60 (m, 9H), 3.71 (s, 3H);

    
    
        LC-MS: Rt=2.05 min, m/z: 550 [M+H]+
    
    


Example 82




7-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (80 mg, 0.20 mmol) and diisopropyl ethylamine (35 μl, 0.40 mmol) in acetonitrile (10 ml) at room temperature as added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (69 mg, 0.2 mmol). The solution was stirred for 12 hours at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with 20% ethyl acetate/hexane to yield 42 mg (33%) of 2-amino-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3): δ 7.64 (d, 1H, J=8.8 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.10–6.80 (m, 5H), 6.09 (s, 2H), 5.04.2 (m, 4H), 3.80 (s, 3H), 3.66–2.92 (m, 3H), 1.55 (s, 9H), 1.04 (s, 9H), 0.22 (s, 6H).
To a stirred solution of 2-amino-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (40 mg, 0.060 mmol) in tetrahydrofuran (1 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (59 mg, 0.30 mmol) in tetrahydrofuran (1 ml). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 ml) and the solution was washed with 0.5 N hydrochloric acid (2×20 ml), saturated sodium bicarbonate (2×20 ml), brine (20 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo and the residue was chromatographed using a gradient of 10–20% ethyl acetate/Hexane as eluent, which afforded 40 mg (83%) of 2-(tert-butoxyoxalyl-amino)-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.52 (s, 1H), 7.37 (t, 1H, J=8.0 Hz), 6.97 (d, 2H, J=8.4 Hz), 6.94 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.54 (d, 1H, J=8.4 Hz), 4.26 (d, 1H, J=16.8 Hz), 3.93–3.84 (m, 2H), 3.77 (d, 1H, J=16.8 Hz), 3.69 (s, 3H), 3.66–3.48 (m, 3H), 3.42–3.32 (m, 1H), 2.95 (dd, 1H, J=14.4 Hz and J=4.8 Hz), 2.92–2.82 (m, 1H), 2.73 (dd, 1H, J=14.4 Hz and J=4.8 Hz), 1.60 (s, 9H), 1.59 (s, 9H), 1.02 (s, 9H), 0.22 (d, 6H, J=1.6 Hz).
To a solution of 2-(tert-butoxyoxalyl-amino)-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (4.0 mg, 5.1 μmol) in 10% formic acid/methanol (1 ml) at room temperature under nitrogen was added 10% Pd/C (4 mg). The mixture was stirred for 1 hour. The Pd/C was filtered off and the filtrate was evaporated in vacuo to afford 2.8 mg (82%) of 2-(tert-butoxyoxalyl-amino)-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-5H-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.45 (s, 1H), 8.05 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 6.99 (d, 1H, J=8.0 Hz), 6.79 (d, 1H, J=8.0 Hz), 4.50 (d, 1H, J=17.2 Hz), 4.45 (d, 1H, J=17.2 Hz), 4.24 (d, 1H, 8.4 Hz), 4.03 (dd, 1H, J=16.0 Hz and J=7.2 Hz), 3.78–3.68 (m, 2H), 3.38–3.28 (m, 1H), 3.21 (d, 1H, J=18.8 Hz), 3.08–2.98 (m, 1H), 1.57 (s, 9H), 1.56 (s, 9H), 0.98 (s, 9H), 0.15 (d, 6H, J=1 Hz).
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was added 2-(tert-butoxyoxalyl-amino)-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-5H-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (2.8 mg, 0.0042 mmol). The solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was washed with dichloromethane affording 1.8 mg (79%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ12.30 (s, 1H), 9.76 (s, 1H), 9.40 (s, 1H), 8.95 (s, 1H), 7.40 (t, 1H, J=7.6 Hz), 7.00 (d, 1H, J=7.6 Hz), 6.83 (d, 1H, J=7.6 Hz), 4.92 (s, 1H), 4.54 (d, 1H, J=18.4 Hz), 4.40 (d, 2H, J=18.4 Hz), 4.08–4.00 (m, 1H), 3.91 (d, 1H, J=15.2 Hz), 3.60 (s, 2H), 3.06 (s, 2H);
LC-MS: Rt: 1.41 min, m/z: 432 [M+H]+
Example 83




7-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was added 2-(tert-butoxyoxalyl-amino)-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (10 mg, 0.013 mmol). The solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was washed with dichloromethane, which afforded 6.8 mg (92%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ12.35 (s, 1H), 9.90 (s, 1H), 9.70 (s, 2H), 7.41 (t, 1H, J=8.0 Hz), 7.28 (s, 2H), 7.04 (d, 1H, J=7.2 Hz), 6.92 (s, 2H), 6.83 (d, 1H, J=7.2 Hz), 4.90–3.60 (m, 11H), 3.80 (s, 3H).
LC-MS: Rt=1.92 min, m/z: 552 [M+H]+
Example 84




7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a stirred solution of 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (10 mg, 0.019 mmol) in tetrahydrofuran (1.0 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (18 mg, 0.092 mmol) in tetrahydrofuran (1.0 ml). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 ml) and washed with 0.5 N hydrochloric acid solution (2×10 ml), saturated sodium bicarbonate (2×10 ml), brine (10 ml), dried (MgSO4), and filtered. The solvent was removed in vacuo and the residue was chromatographed using a gradient of 10–25% ethyl acetate/hexane as eluent, which afforded 11 mg (89%) of 2-(tert-butoxyoxalyl-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.54 (s, 1H), 7.76 (m, 4H), 6.82 (d, 2H, J=11.6 Hz), 6.33 (d, 2H, J=11.6 Hz), 4.02 (d, 1H, J=14.4 Hz), 3.98 (d, 1H, J=14.4 Hz), 3.62 (s, 3H), 3.62–3.54 (m, 2H), 3.48–3.34 (m, 2H), 3.02–2.70 (m, 3H), 1.60 (s, 9H), 1.59 (s, 9H).
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was added 2-(tert-butoxyoxalyl-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (10 mg, 0.015 mmol). The solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was washed with dichloromethane, which afforded 6.8 mg (80%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6): δ 12.38 (s, 1H), 7.86 (m, 4H), 6.82 (s, 2H), 6.30 (s, 2H), 4.00–2.86 (m, 9H), 3.58 (s, 3H);
LC-MS: Rt=2.02 min; m/z: 550 [M+H]+
Example 85




7-(((5-Benzyloxy-1H-indole-2-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.50 g; 1.2 mmol) was dissolved in N,N-dimethylformamide (20 ml). 1-Hydroxy-7-azabenzotriazole (0.19 g; 1.3 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.3 mmol) and diisopropyl-ethylamine (0.23 ml; 1.3 mmol) were added and the mixture was stirred for 15 min. 5-Benzyloxyindole (0.36 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (20 ml) and added. Diisopropylethylamine (0.23 ml; 1.3 mmol) was added and the mixture was stirred overnight. The solvent was removed in vacuo, the residue dissolved in dichloromethane (30 ml) and the organic phase washed with an aqueous solution of sodium hydrogencarbonate (15 ml). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica using ethyl acetate/heptane (1:1) as eluent affording 569 mg of 2-amino-7-(((5-benzyloxy-1H-indole-2-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
The title compound was prepared in a similar way as described in Example 48 using the last two steps.
MS: m/z: 669.4[M+H]+
Calculated for C35H32N4O8S, 2⁄3×C2HF3O2, 4/3×H2O; C, 56.77%; H, 4.63%; N, 7.29%. Found: C, 56.43%; H, 4.57%; N, 7.13%.
Example 86




7-(((6-Bromo-2-p-tolyl-quinoline-4-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 6-bromo-2-p-tolyl-quinoline-4-carboxylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid-tert-butyl ester as the starting material.
LC-MS: m/z: 745.2 [M+H]+
Calculated for C36H31BrN4O7S, 2×C2HF3O2; C, 49.44%; H, 3.42%; N, 5.77%. Found: C, 49.19%; H, 3.59%; N, 6.00%.
Example 87




6-(4-Methoxy-benzyl)-7-(((5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)amino)-methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 605.2 [M+H]+
Calculated for C29H28N6O7S, 1.3×C2HF3O2, 1.7×H2O; C, 48.14%; H, 3.94%; N, 10.94%. Found: C, 48.35%; H, 4.19%; N, 10.68%.
Example 88




7-(((1H-Indole-3-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 3-indole-carboxylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 563.2 [M+H]+
Calculated for C28H26N4O7S, 5/3×C2HF3O2; C, 49.63%; H, 3.82%; N, 7.35%. Found: C, 50.00%; H, 3.71%; N, 7.44%.
Example 89




7-((4-Ethoxy-2-hydroxy-benzoylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 4-ethoxy-2-hydroxy-benzoic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z 584 [M+H]+
HPLC: (B6): 23.8 min.
Example 90




7-((4-Benzoylamino-benzoylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 4-benzoylaminobenzoic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 643.1 [M+H]+
Calculated for C33H30N4O8S, 3×C2HF3O2; C, 47.57%; H, 3.38%; N, 5.69%. Found: C, 47.34%; H, 3.55%; N, 5.62%.
Example 91




7-(((Biphenyl-4-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 4-phenylbenzoic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 599.0 [M+H]+
Calculated for C32H29N3O7S, 2×C2HF3O2, 1×H2O; C, 51.13%; H, 3.93%; N, 4.97%. Found: C, 52.02%; H, 4.02%; N, 5.16%.
Example 92




7-(((1H-Indole-2-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using indole-2-carboxylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 563.2 [M+H]+
HPLC (B6) Rt=23.07 min.
Example 93




7-((3-Biphenyl-4-yl-acryloylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c)pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 3-biphenyl-4-yl-acrylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 626.2 [M+H]+
HPLC (B6) Rt=28.74 min.
Calculated for C34H31N3O7S, 2×C2HF3O2; C, 53.46%; H, 3.90%; N, 4.92%. Found: C, 53.89%; H, 4.23%; N, 5.08%.
Example 94




6-(4-Methoxy-benzyl)-7-(((5-methoxy-1H-indole-2-carbonyl)amino)-methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 5-methoxyindole-2-carboxylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 593.2 [M+H]+
HPLC (B6) Rt=21.81 ml.
Example 95




7-((4-Benzyl-benzoylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 4-benzylbenzoic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z 614.2 [M+H]+
HPLC (B6) Rt=27.23 min.
Calculated for C33H31N3O7S, 1.5×C2HF3O2, 1×H2O; C, 53.87%; H, 4.33%; N, 5.23%. Found: C, 53.92%; H, 4.24%; N, 5.18%.
Example 95




6-(4-Methoxy-benzyl)-7-(((naphthalene-1-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as in Example 84 using 1-napthylcarboxylic acid and 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as the starting material.
LC-MS: m/z: 574.0 [M+H]+
HPLC (B6) Rt=22.51 min.
Calculated for C30H27N3O7S, 2×C2HF3O2; C, 50.94%; H, 3.65%; N, 5.24%. Found: C, 51.39%; H, 3.79%; N, 5.16%.
Example 96




6-(4-Methoxy-benzyl)-5-((2-naphthalen-2-yl-ethylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 2-naphthalen-2-yl-ethanol (1.02 g, 5.8 mmol), 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (9 mg, 0.058 mmol) and sodium bromide (0.65 g, 6.4 mmol) in a mixture of toluene (18 mL), ethyl acetate (18 mL), and water (3 mL) was cooled to 0° C. and added dropwise over 1 hour a solution containing the following: sodium hypochlorite (17.2 mL, 0.37 M, 6.4 mmol) and sodium hydrogencarbonate (1.46 g, 17.4 mmol). The reaction mixture was stirred at 0° C. for 10 min., and the phases separated. The aqueous layer was extracted with ethyl acetate (150 mL). The combined organic phases were washed with a solution of potassium iodone (0.2 g) in 10,% aqueous potassium hydrogensulfate (150 mL), water (150 mL), brine (150 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide 980 mg of a 3:1 mixture of naphthalen-2-yl-acetaldehyde and 2-naphthalen-2-yl-ethanol.
1H-NMR (CDCl3): δ 9.81 (t, 1H, J=1.5 Hz), 7.92–7.80 (m, 3H), 7.68 (bs, 1H), 7.55–7.42 (m, 3H), 3.87 (d, 2H, J=1.5 Hz).
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (290 mg, 0.71 mmol) in 1,2-dichloroethane (3 ml) was added the above mixture of 2-naphthyl-acetaldehyde (100 mg, 0.59 mmol), sodium triacetoxyborohydride (190 mg, 0.88 mmol) and the mixture was stirred at room temperature under nitrogen for 2.5 hours. The crude reaction mixture was quenched with saturated sodium bicarbonate (50 ml) and the solution extracted with ethyl acetate (100 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo providing a foam, which was taken directly to the next step. LC-MS showed that 2-amino-6-(4-methoxy-benzyl)-5-((2-naphthalen-2-yl-ethylamino)-methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was the major component.
LC-MS: m/z: 558.1 [M+H]+, Rf=2.23 min.
To a solution of 2-amino-6-(4-methoxy-benzyl)-5-((2-naphthalen-2-yl-ethylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl-ester in tetrahydrofuran (3 ml) was added di-tert-butyl-dicarbonate (188 mg, 0.85 mmol) and N,N-dimethylformamide (18 mg, 0.14 mmol). The reaction was stirred at room temperature for 7 hours under nitrogen. The crude reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml) and brine-(50 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo affording a foam, which was used without further purification in the next step.
LC-MS showed that 2-amino-5-((tert-butoxycarbonyl-(2-naphthalen-2-yl-ethyl)-amino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was the major component. Rf=2.74, m/z: 658.1 [M+H]+, Calculated: 657.4.
To crude 2-amino-5-((tert-butoxycarbonyl-(2-naphthalen-2-yl-ethyl)-amino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was added dichloromethane (5 ml) and imidazol-1-yl-oxo-acetic acid tert-butyl ester (400 mg, 1.78 mmol) and the reaction mixture stirred at room temperature for 12 hours. The crude reaction mixture was added to dichloromethane (50 ml) and washed with water (50 ml) and brine (50 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography using a mixture of dichloromethane/ethyl acetate (10:1) as eluent; which afforded 20.3 mg (39% over tree steps) of 2-(tert-butoxyoxalyl-amino)-5-((tert-butoxycarbonyl-(2-naphthalen-2-yl-ethyl)-amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a foam.
1H NMR (CDCl3) δ 7.99–7.92 (m, 3H), 7.88 (s, 1H), 7.68–7.57 (m, 3H), 7.45 (d, 2H, J=7.8 Hz), 6.99 (d, 2H, J=8.1 Hz), 3.90–3.75 (m, 7H), 3.56–3.42 (m, 5H), 3.19–3.13 (m, 2H), 2.88–2.82 (m, 2H), 1.79 (s, 9H), 1.71 (s, 18H);
LC-MS: m/z: 786.2 [M+H]+, Rf=3.03 min.
To a solution of 2-(tert-butoxyoxalyl-amino)-5-((tert-butoxycarbonyl-(2-naphthalen-2-yl-ethyl)-amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) in dry dichloromethane (200 μl) at 0° C. was added 50% trifluoroacetic acid in dichloromethane (2.5 ml). The reaction was stirred for 14 hours at room temperature and then concentrated in vacuo. The resultant solid was re-suspended in dichloromethane, filtered, and dried in vacuo to provide 13 mg (90%) of the title compound as a solid.
1H NMR-(DMSO-d6)δ 9.15 (s, 1H), 8.09–8.01 (m, 3H), 7.93 (s, 1H), 7.68–7.57 (m, 3H), 7.45 (d, 2H, J=7.8 Hz), 6.99 (d, 2H, J=8.1 Hz), 4.18–4.12 (m, 2H), 3.90–3.75 (m, 7H), 3.56–3.42 (m, 3H), 3.19–3.13 (m, 2H), 2.88–2.82 (m, 2H);
LC-MS: m/z: 574.7 [M+H]+, Rf=1.36 min.
Example 97




5-((2-Benzo[1,3]dioxol-5-yl-acetylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a mixture of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol), benzo[1,3]dioxol-5-yl-acetic acid (134 mg, 0.74 mmol), 1-hydroxybenzotriazole hydrate (111 mg, 0.82 mmol), and N,N-diisopropyl-ethylamine (258 μL, 1.48 mmol) in acetonitrile (5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol). The reaction mixture was stirred for 16 hours and the solvent evaporated in vacuo. The residue was taken into ethylacetate (50 ml), washed with water, 1 N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a gradient of 10–20% ethylacetate/hexanes as eluent, which afforded 268 mg (64%) of 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 6.95 (bs, 2H), 6.75–6.85 (m, 5H), 5.96 (bs, 2H), 5.95 (s, 2H), 3.81 (s, 3H), 3.75–3.30 (m; 5H), 3.53 (s, 2H), 3.18 (bs, 2H), 2.82 (d, 1H, J=17 Hz), 2.52 (d, 1H, J=17 Hz).
To a solution of 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (133 mg, 0.235 mmol) in tetrahydrofuran (1 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (100 mg, 0.51 mmol). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was taken into ethyl acetate (50 ml) washed with saturated sodium bicarbonate, brine, dried (Na2SO4) and filtered. The solvent was removed in vacuo and the residue was chromatographed using a gradient of 10–20% ethyl acetate/dichloromethane, which afforded 130 mg (80%) of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.95–7.75 (m, 7H), 5.96 (s, 2H), 3.81 (s, 3H), 3.80–3.40 (m, 5H), 3.15 (bs, 2H), 2.90 (d, 1H, J=17 Hz), 2.58 (d, 1H, J=17 Hz), 1.61 (s, 9H), 1.60 (s, 9H).
A solution of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (130 mg, 0.188 mmol) in tetrahydrofuran (2 ml) was passed through a Raney Ni bed (120 mg, 50% Raney Ni-water washed with methanol (6 ml) and tetrahydrofuran (6 ml) and dried before use). The Raney Ni bed was washed with tetrahydrofuran (10 ml). The filtrate and washes were combined and the solvent evaporated in vacuo. The residue was dissolved in 10% formic acid/methanol (6 ml) and stirred with 10% Pd/C (120 mg) for 13 hours. Saturated sodium bicarbonate solution (60 ml) was added to the solution. The mixture was extracted with dichloromethane. The extracts were combined, dried (Na2SO4) and filtered. The solvent was removed in vacuo and the residue was washed with 50% hexane/diethyl ether to afford 62 mg (57%) of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.59 (s, 1H), 6.80–6.70 (m, 3H), 5.96 (s, 2H), 4.05 (q, 2H, J=15 Hz), 3.85–3.60 (m, 2H), 3.25–3.00 (m, 4H), 2.58 (m, 1H), 1.61 (s, 9H), 1.59 (s, 9H);
LC-MS: R=1.75 min, m/z: 574 [M+H]+.
A solution of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (62 mg, 0.11 mmol) in 50% trifluoroacetic acid-dichloromethane (2 ml) was left in an open flask over the weekend and then the solvent was removed in vacuo. The residue was washed with dichloromethane and the solid filtered off affording 39 mg (62%) of the title compounds as a solid trifluoroacetate.
1H-NMR (DMSO-d6) δ 12.39 (s, 1H), 9.18 (bs, 1H), 9.10 (bs, 1H), 8.35 (s, 1H), 6.83 (d 1H, J=1.2 Hz), 6.82 (d, 1H, J=8.4 Hz), 6.70 (dd, 1H, J=8.4 Hz and J=1.2 Hz), 5.96 (s, 2H), 4.38 (d, 1H, J=14 Hz), 4.28 (m, 1H), 3.60–3.40 (m, 4H), 3.16 (d, 2H, J=14 Hz), 2.80 (dd, 1H, J=14 Hz and J=11 Hz);
LC-MS: Rt=1.11 min, m/z: 462 [M+H]+.
Example 98




5-((2-Dibenzofuran-2-yl-ethyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-dibenzofuran-2-yl-ethanol (200 mg, 0.94 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (2 mg, 0.009 mmol) in dichloromethane (2 mL) was added an aqueous solution of sodium bromide (97 mg in 1.3 mL of water for a 0.7M solution, 0.94 mmol) and cooled to 0° C. To this mixture was added dropwise over 30 min., a solution containing the following: sodium hypochlorite (1.4 mL, 0.74 M, 1.03 mmol) and sodium hydrogencarbonate (120 mg, 1.4 mmol) and water (1.4 mL). The reaction mixture was stirred at 0° C. for 0.5 hour and allowed to warm to room temperature. The organic phase and aqueous layer were separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic phases were washed with a solution of potassium iodone (0.2 g) in 10% aq. Potassium hydrogensulfate (20 mL), water (20 mL), brine (20 mL), dried (MgSO4) filtered, and concentrated in vacuo to provide 198 mg of a 5:1 mixture of dibenzofuran-2-yl-acetaldehyde and 2-dibenzofuran-2-yl-ethanol as an oil.
1H-NMR (CDCl3): δ 9.80 (t, 1H, J=1.5 Hz), 8.02 (d, 2H, J=8.2 Hz), 7.71 (bs, 1H), 7.75–7.42 (m, 4H), 3.82 (d, 2H, J=1.5 Hz).
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (340 mg, 0.85 mmol) in 1,2-dichloroethane (3 ml) was added the above mixture of dibenzofuran-2-yl-acetaldehyde (150 mg, 0.70 mmol), and sodium triacetoxyborohydride (225 mg, 1.07 mmol) and the mixture was stirred at room temperature under nitrogen for 2.5 hours. The crude reaction mixture was quenched with saturated sodium bicarbonate (50 ml) and the solution extracted with ethylacetate (100 ml). The organic phase dried (MgSO4), filtered, and the solvent evaporated in vacuo. The crude residue was taken directly to the next step. LC-MS showed that 2-amino-5-((2-dibenzofuran-2-yl-ethylamino)methyl]-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was the major component in the crude mixture: m/z: 598.1 [M+H]+, Rf=2.40 min).
Crude 2-amino-5-((2-dibenzofuran-2-yl-ethylamino)methyl]-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was diluted in tetrahydrofuran (3 ml) and di-tert-butyl dicarbonate (262 mg, 1.20 mmol) and 4-(N,N-dimethylamino)pyridine (25 mg, 0.20 mmol) were added. The reaction was stirred at room temperature for 7 hours under nitrogen. The crude reaction mixture was added to dichloromethane (50 ml) and washed with water (50 ml) and brine (50 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was used directly in the next step. LC-MS showed that 2-amino-5-((tert-butoxycarbonyl-(2-dibenzofuran-2-yl-ethyl)amino)-methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was the major component in the crude: Rf=2.76, m/z: 698.2 [M+H]+.
To compound 2-amino-5-((tert-butoxycarbonyl-(2-dibenzofuran-2-yl-ethyl)amino)-methyl)-6-(4′-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was added dichloromethane (5 ml) and imidazol-1-yl-oxo-acetic acid tert-butyl ester (420 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 12 hours. The crude reaction mixture was added to dichloromethane (50 ml) and washed with water (50 ml) and brine (50 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of dichloromethane/ethyl acetate (10:1) as eluent, which afforded 35.2 mg (51% over 3 steps) of 2-(tert-butoxyoxalyl-amino)-5-((tert-butoxycarbonyl-(2-dibenzofuran-2-yl-ethyl)amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a foam.
1H-NMR (CDCl3) δ 7.95–7.90 (m, 3H), 7.84 (s, 1H), 7.68–7.57 (m, 3H), 7.45 (d, 2H, J=7.8 Hz), 6.95 (m, 3H), 3.90–3.75 (m, 7H), 3.56–3.42 (m, 5H), 3.19–3.13 (m, 2H), 2.88–2.82 (m, 2H), 1.79 (s, 9H), 1.71 (s, 18H);
LC-MS: Rf=3.03 min, m/z: 826.2 [M+H]+.
To a solution of 2-(tert-butoxyoxalyl-amino)-5-((tert-butoxycarbonyl-(2-dibenzofuran-2-yl-ethyl)amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (28 mg, 0.034 mmol) in dry dichloromethane (200 μL) at 0° C. was added 50% trifluoroacetic acid in dichloromethane (2.5 ml). The reaction was stirred for 14 hours at room temperature and then concentrated in vacuo. The resultant solid was re-suspended in dichloromethane, filtered, and dried in vacuo, which afforded 22 mg (90%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6), δ9.15 (s, 1H), 8.11–8.21 (m, 3H), 7.93 (s, 1H), 7.68–7.57 (m, 3H), 7.45 (d, 2H, J=7.8 Hz), 6.99 (d, 2H, J=8.1 HZ), 4.18–4.12 (m, 2H), 3.90–3.75 (m, 7H), 3.56–3.42 (m, 3H), 3.19–3.13 (m, 2H), 2.88–2.82 (m, 2H);
LC-MS: Rf=3.03, m/z: 614.7 [M+H]+.
Example 99




6-(4-Methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)-acetylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (202 mg, 0.50 mmol), in N,N-dimethylformamide (4 ml) was added 5-methoxy-2-methyl-3-indole acetic acid (170 mg, 0.74 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide, hydrochloride (150 mg, 0.75 mmol), and 1-hydroxybenzotriazole (105 mg, 0.74 mmol). The mixture was stirred at room temperature for 12 hours. The crude reaction mixture was diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo, which afforded 2-amino-6-(4-methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 7.16 (d, 2H, J=10.8 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.94 (m, 1H), 6.85 (dd, 1H, J=8.4 Hz and J=1.2 Hz), 6.78 (dd, 1H, J=8.3 Hz and J=1.2 Hz), 6.65 (m, 3H), 6.57 (m, 4H), 3.57 (t, 4H, J=3.0 Hz), 3.53 (m, 6H), 3.59–3.29 (m, 5H), 3.12–2.92 (m, 4H), 2.39 (s, 3H), 1.6 (s, 9H);
LC-MS Rt=2.19, m/z: 605 [M+H]+.
To a solution of 2-amino-6-(4-methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (96 mg, 0.5 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (583 mg, 3.0 mmol) and the reaction stirred at room temperature for 24 hours. The mixture was then concentrated in vacuo. The residue was purified by flash column chromatography (25% ethylacetate/dichloromethane) to give 53 mg (15. %) of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 7.16 (d, 2H, J=10.8 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.94 (m, 1H), 6.85 (dd, 1H, J=8.4 Hz and J=1.2 Hz), 6.78 (dd, 1H, J=8.3 Hz and J=1.2 Hz), 6.65 (m, 3H), 6.56 (m, 3H), 3.57 (m, 3H), 3.53 (m, 6H), 3.59–3.29 (m, 5H), 3.12–2.92 (m, 4H), 2.39 (s, 3H), 1.6 (s, 18H);
LC-MS Rt=2.36 min, m/z: 733 [M+H]+.
2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was dissolved in 50% trifluoroacetic acid/dichloromethane (3 ml) and stirred at room temperature for 48 hours. The solvent was removed in vacuo and the residual trifluoroacetic acid was removed under reduced pressure to give 17 mg (49%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6) δ 10.62 (s, 1H), 7.31 (s, 1H), 7.08 (d, 1H, J=10.2 Hz), 6.93 (s, 2H), 6.58 (dd, 1H, J=5.25 Hz and J=2.8 Hz), 3.84–3.44 (m, 19H, partially obscured by solvent), 2.95 (s, 1H), 2.28 (s, 3H), 1.31 (s, 1H), 1.19 (s, 2H);
LC-MS-Rt=1.89 min, m/z: 621 [M+H]+.
Example 100




5-((2-(1H-Indol-3-yl)-2-oxo-acetylamino)methyl)-2-(Oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (209 mg, 0.51 mmol) in dry N,N-dimethylformamide (4 ml) was added 3-indole-glyoxylic acid (141 mg, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (152 mg, 0.76 mmol), and 1-hydroxy-benzotriazole (100 mg, 0.74 mmol). The mixture was stirred at room temperature for 16 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 143 mg (40. %) of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
LC-MS Rt=2.31 min, m/z: 574.9 [M+H]+.
To a solution of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (143 mg, 0.25 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (144 mg, 0.75 mmol) and the flask was purged with nitrogen. After 24 hours an additional portion of imidazol-1-yl-oxo-acetic acid tert-butyl ester (169 mg, 0.86 mmol) was added and the reaction mixture allowed stirred for an additional 24 hours. The mixture was then concentrated in vacuo. The residue was purified by flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 101 mg (58%) of 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a oil.
1H-NMR (CDCl3) δ 9.23 (s, 1H); 9.07 (d, 1H, J=3.6 Hz), 8.50 (d, 1H, J=7.6 Hz), 8.15 (d, 1H, J=4.0 Hz), 7.47 (d, 2H, J=7.2 Hz), 7.38–7.27 (m, 6H), 6.89 (d, 2H, J=8.8 Hz), 3.87–3.59 (m, 6H), 3.04 (dd, 2H, J=23.6 Hz), 2.74 (dd, 2H, J=22.4 Hz), 1.62 (s, 18H);
LC-MS Rt=2.49 min, m/z: 703 [M+H]+.
2-(tert-Butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (101 mg, 0.143 mmol) was dissolved in dry tetrahydrofuran (6 ml) and passed through a pipette, plugged with cotton containing Raney 2800 Nickel (0.38 g). The pipette was flushed with dry tetrahydrofuran (6 ml) and the filtrate was concentrated in vacuo. Pd on carbon (10%, 102 mg, source: Avocado) and formic acid (10% in methanol, 5 ml) were added to the flask containing 2-(tert-Butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester. After stirring for 18 hours, the solution was filtered through a pad of celite and concentrated in vacuo. The residue was diluted in ethyl acetate, washed with saturated sodium bicarbonate (2×25 ml), brine (2×25 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of 10% methanol/dichloromethane as eluent, which afforded 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
1H-NMR (CDCl3) δ 9.23 (s, 1H), 9.07 (d, 1H, J=3.6 Hz), 8.50 (d, 1H, J=7.6 Hz), 8.15 (d, 1H, J=4.0 Hz), 7.27 (s, 2H), 7.09 (d, 1H, J=8.8 Hz), 6.81 (d, 1H, J=8.8 Hz), 3.79 (s, 1H), 2.29 (s, 1H), 1.62–1.57 (m, 18H), 0.08 (s, 5H);
LC-MS: Rt=2.17 min, m/z: 583 [M+H]+.
The above 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was dissolved in 50% trifluoroacetic acid/dichloromethane (3 ml) and stirred at room temperature for 18 hours. The solvent was removed in vacuo and residual trifluoroacetic acid was removed under reduced pressure affording 17.1 mg of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6) δ 12.28 (s, 2H), 9.26 (s, 1H), 9.13 (s, 1H), 8.83 (d, 1H, J=2.8 Hz), 8.26 (d, 1H, J=8.8 Hz), 7.55 (d, 0.1H, J=4.8 Hz), 7.27 (d, 2H, J=7.6 Hz), 4.42 (d, 1H, J=15.2 Hz), 4.29 (d, 1H, J=16.4 Hz), 3.76–3.22 (m, 4H, partially obscured by solvent), 2.91–2.834 (m, 1H), 1.23 (s, 1H); LC-MS: Rt=0.99 min, m/z 471.4 [M+H]+.
General Chiral Synthesis
4-Oxo-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester




Dichloromethane (1 L) and mol sieves 3 Å (113 g) and amine (S)-(−)-α-methyl-benzylamin (71.7 ml) were mixed in a 2 l three-necked bottle cooled to −5° C. (using a ethanol/water/ice bath). A 50% solution of ethylglyoxylate in toluene (117.6 ml) was added drop wise over 20 min. keeping the temperature between −5° C. and 0° C. The mixture was stirred for 0.5 hour before it was cooled to −30° C. Trifluoroacetic acid (45.2 ml) was added over 3–4 minutes. Boron trifluoride diethyl ether (69.8 ml) was added drop wise over 5 min at −55° C. The ice bath was removed and the mixture was allowed to warm up to −45° C. whereupon 2-trimethylsiloxy)-1,3-butadiene (100 ml) was added drop wise over 10 minutes. During the addition the mixture was cooled and the temperature kept below −20° C. The above additions are all exothermic hence the cooling bath should have sufficient capacity to remove the heat generated during the rapid addition. The reaction mixture was stirred for 2 hours at −15° C. and 1 hour at 0° C. and then poured on ice/water and stirred for 15 minutes. Solid sodium hydrogen carbonate was added until pH 7–8. The mixture was stirred overnight at room temperature. The layers wee separated and the aqueous phase extracted with dichloromethane. The combined organic phases were filtered through a plug of silica eluting with dichloromethane. The relevant fractions were concentrated in vacuo. The residue was dissolved in hot heptane and cooled. This leaves a yellowish gummy material on the side of the flask and crystals starts forming. The heptane solution was heated again to dissolve crystals, leaving the gummy material on the side of the flask and the mixture was filtered hot. The heptane solution was cooled to room temperature and the precipitate was filtered off and dried in vacuo, which afforded 38 g of 4-oxo-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester as a solid.
The filtrate was put in a refrigerator and a second crop was formed which was less pure and needed recrystallization from heptane to yield another 7.5 g of 4-oxo-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester.
4,4-Diethoxy-1-((S)-1-phenyl-ethyl)-piperidine-(S)-2-carboxylic acid ethyl ester




The mother liquor from the above crystallization was concentrated in vacuo. 5.0 g of the resulting material (18.16 mmol) was dissolved in ethanol (100 ml) and triethylorthoformate (26.9 g, 181.6 mmol) and para-toluensulphonic acid (6.9 g, 36.32 mmol) was added. The reaction was stirred at room temperature for 16 hours before the mixture was poured on aqueous sodium hydrogen carbonate (200 ml) and extracted with ethyl acetate (4×75 ml). The combined extracts were concentrated in vacuo and purified by column chromatography (SiO2, Flash 40, petrol ether-ethyl acetate-10:1). Collection of the first band (Rf=0.68) gave 1.14 g (18%) of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester and collection of the second band (Rf=0.4) gave 3.60 g (57%) of the title compound.
4,4-Diethoxy-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester




4-Oxo-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester (11.0 g, 0.040 mmol) was dissolved in a 1:1 mixture of triethyl orthoformate and ethanol (140 ml) and para-toluene-4-sulphonic acid (15.2 g, 80 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was neutralized with sodium bicarbonate (to pH 7–8), and extracted with dichloromethane (3×100 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petrol ether/ethyl acetate 10:1), which afforded 12.0 g (86%) of the title compound as an oil.
4,4-Diethoxy-1-((S)1-phenyl-ethyl)-(R)-2-hydroxymethyl-piperidine




To a solution of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester (36.0 g, 0.103 mol) in dry diethyl ether (150 ml) was added a suspension of lithium aluminum hydride (5.88 g, 0.155 mol) in dry diethyl ether (300 ml) under an atmosphere of nitrogen at such a rate that the solution gently reflux. The reaction mixture was stirred over night before it was cooled to 0° C. and ethyl acetate (30 ml) was added drop wise to destroy excess lithium aluminum hydride. After stirring for another 0.5 hour, water (12 ml) was added drop wise. After stirring for 10–15 min the precipitate was filtered off through celite and the filter cage was washed with plenty of diethyl ether. The filtrate was washed with brine (100 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo, which afforded 30 g (95%) of the title compound as an oil.
4,4-Diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-phthalimidomethyl-piperidine




A solution of 4,4-Diethoxy-1-((S)1-phenyl-ethyl)-(R)-2-hydroxymethyl-piperidine (65.35 g, 0.213 mmol), triphenylphosphine (61.3 g, 0.234 mol) and phthalimide (34.4 g, 0.234 mol), in tetrahydrofuran (700 ml) cooled to 0° C. was added diethyl azodicarboxylate over the course of 1.5 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the solvent was removed in vacuo. The residue was dissolved in hot heptane-toluene (3:2) (650 ml) before it was cooled on an ice bath. The precipitate consisting of triphenyl phosphine oxide was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene-ethyl acetate-heptane (3:1:3) as eluent. The solvent was evaporated in vacuo whereupon a viscous oil was obtained. Upon addition of light petrol ether the product crystallized to give 67.4 g (73%) of the title compound as a solid.
Example 101




5-(R)-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A mixture of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-phthalimidomethyl-piperidine (5.25 g, 12.0 mmol) and hydrazine hydrate (2.92 ml, 60 mmol) was stirred overnight in ethanol (100 ml) at room temperature. The solvent was removed in vacuo and the solid residue was extracted with refluxing diethyl ether. The diethyl ether fractions were combined and evaporated in vacuo, which afforded 3.94 g (94%) of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-aminomethyl-piperidine as an oil.
4,4-Diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-aminomethyl-piperidine (2.25 g, 7.37 mmol), and triethyl amine (1.49 g, 14.7 mmol) in acetonitrile (50 ml) was heated to 60° C. before 2-chlormethyl-6-methoxy-benzoic acid methyl ester (1.58 g, 7.37 mmol) in acetonitrile (25 ml) was added over the course of 1.5 hour. After addition the reaction mixture was stirred overnight at 60° C. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 ml) and washed with saturated sodium bicarbonate. After drying (MgSO4), filtration and evaporation of the solvent in vacuo the residue was subjected to flash column chromatography (SiO2, ethyl acetate-light petrol ether (1:1)) to give 2.3 g (69%) of 2-(R)-(7-methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-piperidine.
2-(R)-(7-Methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4,4-diethoxy-1 (1-(S)-phenyl-ethyl)-piperidine (2.0 g, 4.4 mmol) was dissolved in a ice cold mixture of trifluoroacetic acid and water (10 ml, 9:1) and stirred or 0.5 hour on an ice bath. The reaction mixture was poured on aqueous sodium carbonate (100 ml) and extracted with dichloromethane (2×50 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo, affording 1.67 g (100%) of 2-(R)-(7-methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4-oxo-1 (1-(S)-phenyl-ethyl)-piperidine.
2-(R)-(7-Methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4-oxo-1 (1-(S)-phenyl-ethyl)-piperidine (1.67 g, 4.41 mmol), sulphur (0.155 g, 4.85 mmol), tert-butylcyanoacetate (0.684 g, 4.85 mmol), N-methylmorpholine (0.892 g, 8.82 mmol) and molecular sieves (4 Å, 2 g) was heated to 50° C. in ethanol under an atmosphere of nitrogen for 16 hours. The reaction mixture was filtered through a plug (1 cm) of SiO2, the silica was washed with dichloromethane-ethyl acetate and the solvent was removed in vacuo. The resulting residue was subjected to column chromatography (Flash 40, SiO2, toluene-ethyl acetate (3:1)). Which yielded 1.17 g (50%) of 2-amino-5-(R)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester and 2-amino-7-(S)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a 3:1 mixture.
The above mixture of 5- and 7-regioisomers (1.17 g, 2.19 mmol) and imidazol-2-yl-oxo-acetic acid tert-butyl ester (1.29 g, 7.57 mmol) and triethylamine (0.66 g, 6.57 mmol) was stirred under an atmosphere of nitrogen in dichloromethane (25 ml) for 16 hours. The solvent was removed in vacuo and the residue was subjected to column chromatography (SiO2, Flash 40, ethyl acetate-petrol ether (1:1)).
Collection of relevant fractions gave 0.61 g (42%) of 2-(tert-butoxyoxalyl-amin)-5-(R)-(7-methoxy-1-oxo-1,3-dihydro-isoindo-2-ylmethyl)-6-(1-(S)-phenyl-ethyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
2-(tert-Butoxyoxalyl-amin)-5-(R)-(7-methoxy-1-oxo-1,3-dihydro-isoindo-2-ylmethyl)-6-(1-(S)-phenyl-ethyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.60 g, 0.91 mmol) was stirred for 16 hours in a mixture of methanol and formic acid (10:1) (20 ml) in the presence of 10% palladium on carbon (50% water). The reaction mixture was filtered through a plug of Celite and washed with methanol. The volatiles were removed in vacuo and the residue was dissolved in dichloromethane (50 ml), washed with semi saturated aqueous sodium carbonate (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (SiO2, Flash 40, ethyl acetate-methanol (100:15)), which afforded 0.36 g (71%) of 2-(tert-butoxyoxalyl-amin)-5-(R)-(7-methoxy-1-oxo-1,3-dihydro-isoindo-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
2-(tert-Butoxyoxalyl-amin)-5-(R)-(7-methoxy-1-oxo-1,3-dihydro-isoindo-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (349 mg, 0.63 mmol) was stirred for 16 hours in a mixture of trifluoroacetic acid and dichloromethane (1:1) (10 ml) whereupon diethyl ether (20 ml) was added. The precipitate was filtered off and washed with diethyl ether, which afforded 215 mg (61%) of the title compound as a solid trifluoroacetate.
LC-MS: Rt=1.17 min, m/z: 446 [M+H]+
Calculated for C20H19N3O7S, C2HF3O2, 0.5×H2O C, 46.48%; H, 3.72%; N, 7.39%; Found: C, 46.45%; H, 3.97%; N, 7.43%;
Example 102




5-(S)-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-piperidine-(S)-2-carboxylic acid ethyl ester (35.98 g, 0.103 mol) in diethyl ether (150 ml) was added drop wise to a suspension of lithium aluminum hydride (5.88 g, 0.155 mol) in diethyl ether (300 ml) over the course of 1 hour. The reaction mixture was stirred at room temperature overnight before it was cooled on an ice bath and the reaction was quenched by dropwise addition of ethyl acetate (30 ml), followed by drop wise addition of water (12 ml) whereupon a gray precipitate was formed. The mixture was filtered through a plug of Celite and the filter cage was washed with plenty of diethyl ether. The filtrate was dried (MgSO4) before it was filtered and the solvent removed in vacuo, which afforded 24.5 g (79%) of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-(S)-2-hydroxymethyl-piperidine as an oil.
A suspension of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-(S)-2-hydroxymethyl-piperidine (20 g, 65 mmol), triphenylphosphine (18.76 g, 72 mmol) and phthalimide (10.52 g, 72 mmol) in tetrahydrofurane (200 ml) cooled to 0° C. was added diethyl azodicarboxylate (11.34 ml, 72 mmol) over the course of 1 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the volatiles were removed in vacuo. The residue was dissolve in hot heptane-toluene (3:2) (100 ml) before it was cooled on an ice bath. The precipitate was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene/ethyl acetate/heptane (3:1:3) as eluent. The solvent was evaporated in vacuo and the residue was crystallized by addition of light petrol ether (250 ml). The precipitate was filtered off, which afforded 24 g (85%) of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine as a solid.
4,4-Diethoxy-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine (4.0 g, 9.2 mmol) was dissolved in a mixture of trifluoroacetic acid and water (9:1) (100 ml) at 0° C. and stirred for 2 hours at this temperature. The mixture was basified with half saturated aqueous sodium carbonate, extracted with ethyl acetate and dried (MgSO4) for 2 hours. The solvent was removed in vacuo and the residue was dried in a vacuum own at 40° C. for to days. This afforded 3.23 g (98%) of 4-oxo-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine pure without further purification (98%). A mixture of 4-oxo-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine (17.28 g, 47.73 mmol), tert-butylcyanoacetat (7.41 g, 52.17 mmol), sulphur (1.71 g, 52.17 mmol) and morpholine (8.31 g, 95.46 mmol) in ethanol (150 ml) was heated under an atmosphere of nitrogen at 50° C. The volatiles were removed in vacuo and the residue was subjected to column chromatography on silica gel (heptane-ethyl acetate 5:1). The fractions consisting of a mixture of 5- and 7-isomer were collected and the solvent evaporated in vacuo. The residue was purified on a reverse phase (C18) column using a Flash 40 system. The residue was applied in a minimum volume of acetonitrile and eluted with 40% acetonitrile in water containing 0.1% trifluoroacetic acid. When the 5-isomer was collected the eluent was changed to 50% acetonitrile in water with 0.1% trifluoroacetic acid and the 7-isomer was collected. Yield of 2-amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4, 5, 6, 7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was 7.96 g and yield of 2-amino-7-(R)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester was 3.72 g (47% total).
2-Amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic-acid tert-butyl ester (7.96 g, 15.4 mmol) and hydrazine hydrate (3.85 g, 77.0 mmol) in ethanol (250 ml) was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the solid residue was extracted with diethyl ether (3×200 ml). The fractions were combined and the solvent removed in vacuo to give 5.9 g (100%) of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
2-Amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.55 g, 1.42 mmol) and triethylamine (396 μl, 2.84 mmol) was heated in acetonitrile (15 ml) under an atmosphere of nitrogen to 60° C. whereupon a solution of 2-chloromethyl-6-methoxy-benzoic acid methyl ester (0.32 g, 1.49 mmol) in acetonitrile (5 ml) was added dropwise over the course of 3 hours, keeping the reaction mixture at 60° C. The reaction was allowed to cool to room temperature and was left for 16 hours before the solvent was evaporated in vacuo. The product was purified by column chromatography (SiO2, Flash 40, ethyl acetate-petrol ether) to give 400 mg (53%) of 2-amino-5-(S)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-((S)-1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
The title compound was obtained as a trifluoroacetate in a similar way as described in example 101 using the last three steps.
Example 103




5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic-acid
3-Hydroxy-2-methylbenzoic acid (0.5 g, 3.2 mmol) was dissolved in HPLC grade methanol (5 ml) and cooled to 0° C. under nitrogen. Acetyl chloride (5 ml) was added dropwise. Once the addition was complete, the ice bath was removed and the reaction mixture allowed warming to room temperature over a period of 18 hours. The reaction was complete by tlc (Rf=0.5, 1:1 ethyl acetate/hexanes) and quenched with saturated sodium bicarbonate. The reaction mixture was concentrated, diluted with dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91%) of 3-hydroxy-2-methylbenzoic acid methyl ester as a solid.
1H-NMR (CDCl3) δ 7.39 (dd, 1H, J=8.1 Hz and J=1.5 Hz), 7.09 (t, 1H, J=8.1 Hz), 6.92 (dd, 1H, J=8.1 Hz and J=1.2 Hz), 5.11 (bs, 1H), 3.87 (s, 3H), 2.43 (s, 3H).
3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.
1H-NMR (CDCl3) δ 7.46 (dd, 1H, J=7.6 Hz and J=1.2 Hz), 7.21 (dd, 1H, J=8 Hz and J=1.2 Hz), 7.18 (d, 1H, J=8 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.46 (s, 3H).
To a mixture of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (0.44 g, 2.09 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (0.39 g, 2.19 mmol) and 1,1′-azo bis(cyclohexane-carbonitrile) (0.051 g, 0.21 mmol). The mixture was heated at reflux for 3 hours, at which time the reaction was judged complete by tlc (1:4 ethyl acetate/hexanes). The reaction mixture was cooled to room temperature and concentrated in vacuo to a solid. The solid was recrystallized from hexane leaving 0.44 g (82%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.
1H-NMR (CDCl3) δ 7.58 (dd, 1H, J=6.8 Hz and J=2.4 Hz), 7.33–7.29 (m, 2H), 5.30 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 3.52 (s, 3H).
To a stirred mixture of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.24 g, 0.67 mmol) in acetonitrile (30 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) under nitrogen. 2-Bromo-methyl-3-methoxymethoxy-benzoic acid methyl ester (0.16 g, 0.55 mmol) dissolved in acetonitrile, was added via syringe pump at a rate of 0.3 ml/hour. Once the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. Tlc analysis (1:1 ethyl acetate/hexanes) indicated the reaction to be complete. The volatiles were removed in vacuo and the resultant oil dissolved in ethyl acetate/water. The layers were separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100%) of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester, which was used without further purification in the next step.
1H-NMR (CDCl3) δ 7.51 (d, 1H, J=6.8 Hz), 7.42 (t, 2H, J=7.6 Hz, 7.23–7.17 (m, 5H), 5.93 (s, 2H), 5.25 (s, 2H), 4.23 (s, 2H), 4.12 (q, 1H, J=7.2 Hz), 3.94 (m, 1H), 3.85 (q, 1H, J=6.4 Hz), 3.66 (d, 1H, J=16.4 Hz), 3.50 (s, 3H), 3.48–3.46 (m, 1H), 3.20 (dd, 1H, J=14 Hz and J=6 Hz), 2.94–2.87 (m, 1H), 2.60 (m, 1H), 1.49 (s, 9H), 1.36 (d, 3H, J=6.4 Hz);
LC-MS: m/z: 564.1 [M+H]+.
To a solution of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.34 g, 0.60 mmol) in dichloromethane (10 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.35 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (2×20 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:1) as eluent. The obtained residue was then subjected to chromatotron purification (1% methanol/dichloromethane) and later to another flash chromatography (20% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) to obtain 210 mg (50%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.51 (dd, 1H, J=6.8 Hz and J=1.2 Hz), 7.42 (t, 2H, J=8 Hz), 7.25–7.17 (m, 5H), 5.23 (s, 2H), 4.24 (q, 2H, J=16.8 Hz), 4.08 (d, 1H, J=16.8 Hz), 4.01 (dd, 1H, J=14 Hz and J=8.8 Hz), 3.89 (d, 1H, J=17.6 Hz), 3.82 (q, 1H, J=6.8 Hz), 3.56 (q, 1H, J=6.4 Hz), 3.51 (s, 3H), 2.28 (dd, 1H, J=14 Hz and J=6.4), 2.98–2.92 (m, 1H), 2.69 (d, 1H, J=17.2), 1.56 (s, 9H), 1.54 (s, 9H), 1.38 (d, 3H, J=6.8 Hz);
LC-MS: m/z: 692.5 [M+H]+.
To a solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.16 g, 0.23 mmol) in formic acid (10% in methanol, 5 ml total) was added 10% palladium on carbon (85 mg, source: Avacado) and the reaction mixture allowed to stir at room temperature. After 6 hours, tlc (1:1 ethyl acetate/hexanes) analysis indicated reaction complete. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified via flash chromatography (gradient: 3% isopropyl alcohol/dichloromethane to 5% isopropyl alcohol/dichloromethane (in 1% increments of isopropyl alcohol)) to provide 0.11 g (82%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.50 (bs, 1H), 7.48 (dd, 1H, J=7.6 Hz and J=0.8 Hz), 7.38 (t, 1H, J=8 Hz), 7.22 (dd, 1H, J=8 Hz and J=0.8 Hz); 5.24 (s, 2H), 4.50 (q, 2H, J=17.3 Hz), 4.02–3.90 (m, 2H), 3.74 (ddd, 2H, J=34 Hz, J=13.6 Hz and J=5.6 Hz), 3.49 (s, 3H), 3.24 (m, 1H), 2.97 (ddd, 1H, J=20 Hz, J=4.4 Hz and J=2.8 Hz), 2.50 (m, 1H), 1.59 (s, 9H), 1.51 (s, 9H);
LC-MS: m/z: 587.8 [M+H]+.
2-(tert-Butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.11 g, 0.18 mmol) was dissolved in neat trifluoroacetic acid (4 ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and the resultant solid washed with dichloromethane several times affording 100 mg (83%) of the title compound as a solid trifluoroaceatet.
1H-NMR (DMSO-d6) δ 12.29 (bs, 1H), 10.13 (s, 1H), 9.29 (bs, 1H), 9.10 (bs, 1H), 7.32 (t, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=8 Hz), 4.52 (d, 1H, J=17.2 Hz), 4.40–4.22 (m, 3H), 4.05 (dd, 1H, J=14.4 Hz and J=9.6 Hz), 3.90 (bs, 1H), 3.69 (dm, 1H), 3.22 (dm, 1H), 2.80 (dm,
LC-MS: m/z: 432.2 [M+H]+.
Example 104




2-(S)-(Oxalyl-amino)-5-((4-phenoxy-benzylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (500 mg, 1.29 mmol) and 4-phenoxybenzaldehyde (256 mg, 1.29 mmol) was heated to 50° C. in ethanol (50 ml) for 1 hour in the presence of molecular sieves (4 A, 5 ml). The reaction mixture was cooled on an ice bath before sodium borohydride (98 mg, 2.59 mmol) was added in three portions over 45 min. The cooling bath was removed and the reaction mixture was allowed to reach room temperature. The mixture was filtered through a plug of Celite and the filter cage was washed with dichloromethane 3×25 ml). The solvent was removed in vacuo and the residue was redissolved in ethyl acetate (50 ml), washed with sodium bicarbonate (50 ml) and dried (MgSO4). The solvent was removed in vacuo before the residue was redissolved in acetonitrile (20 ml). Triethylamine (130 mg, 1.29 mmol), di-tert-butyl dicarbonate (282 mg, 1.29 mmol) and 4-(N,N-dimethyl-amino)pyridine (5 mg, cat.) was added and the reaction mixture was stirred for 16 hours at room temperature. The volatiles were removed in vacuo and ethyl acetate (50 ml) was added and the solution was washed with saturated sodium bicarbonate (50 ml) and dried (MgSO4). The crude product was purified by column chromatography (SiO2, petroleum ether-ethyl acetate (9:1)) to give 325 mg (38% overall) of 2-amino-5-(S)-((4-phenoxy-benzylamino)methyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
The title compound was obtained as a trifluoroacetate in a similar way as described in example 96 using the last three steps.
Oxalation: Standard procedure (16 hours, 82%)
Hydrogenolysis: standard procedure (Pd/C, 10% Pd, methanol-formic acid, 16 hours, ((10:1)) (82% yield)
TFA cleavage: Standard procedure. Yield 150 mg (87%).
LC-MS m/z: 482 [M+H]+, Rt=1.87 min
Calculated for C24H23N3O6S, 2×(C2HF3O2) C, 47.40%; H, 3.55%; N, 5.92%; Found: C, 47.47%; H, 3.87%; N, 5.88%.
Example 105




5-(S)-((4-Acetylamino-benzylamino)-methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared as a trifluoroacetate in a similar way as described in Example 96 using 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester and N-(4-formyl-phenyl)acetamide as the starting material.
Calculated for C20H22N4O6S, 1.5×C2HF3O2, 1.5×H2O C, 43.78%; H, 3.99%; N, 8.88%; Found: C, 44.20%; H, 4.43%; N, 8.75%.
Example 106




7-(S)-((Acetyl-(4-phenoxy-benzyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 2-amino-7-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic aicd tert-butyl ester (500 mg, 1.29 mmol) and 4-phenoxybenzaldehyde (256 mg, 1.29 mmol) was heated to 50° C. in ethanol (50 ml) for 1 hour in the presence of molecular sieves (4 A, 5 ml). The reaction mixture was cooled on an ice bath before sodium borohydride (98 mg, 2.59 mmol) was added in three portions over 45 min. The cooling bath was removed and the reaction mixture was allowed to reach room temperature. The mixture was filtered through a plug of Celite and the filter cage was washed with dichloromethane (3×25 ml). The solvent was removed in vacuo and the residue was redissolved in ethyl acetate (50 ml), washed with sodium bicarbonate (50 ml) and dried (MgSO4). The solvent was removed in vacuo before the product was dissolved in dichloromethane (10 ml). The solution was cooled on an ice bath before di-isopropyl-ethyl amine (101 mg, 1.29 mmol) was added followed by drop wise addition of acetyl chloride (101 mg, 1.29 mmol) in dichloromethane (1 ml). The reaction mixture was stirred 1 hour at 0° C. and the solution was washed with sodium bicarbonate (10 ml) and dried (MgSO4). The crude product was purified by flash column chromatography (SiO2, ethyl acetate-petrol ether 1:3) to give 320 mg (41%) of 7-(S)-((acetyl-(4-phenoxy-benzyl)amino)methyl)-2-amino-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was obtained as a trifluoroacetate in a similar way as described in example 96 using the last three steps.
Oxalation: Standard procedure (Yield 69%)
Hydrogenolysis and trifluoroacetic acid cleavage in one step, Standard procedure (Overall yield 6%)
LC-MS m/z=524 [M+H]+, Rt=2.58 min
Calculated for C26H25N3O7S, C2HF3O2, 0.5×H2O C, 52.01%; H, 4.21%; N, 6.50%; Found: C, 51.82%; H, 4.34%; N, 6.36%.
Example 107




7-(S)-((Acetyl-benzyl-amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 2-amino-7-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic aicd tert-butyl ester (400 mg, 1.03 mmol) and benzaldehyde (105 mg, 1.03 mmol) was heated to 50° C. in ethanol (20 ml) for 1 hour in the presence of molecular sieves (4 A, 7 ml). The reaction mixture was cooled on an ice bath before sodium borohydride (78 mg, 2.06 mmol) was added in three portions over 45 min. The cooling bath was removed and the reaction mixture was allowed to reach room temperature. The mixture was filtered through a plug of Celite and the filter cage was washed with dichloromethane (3×25 ml). The solvent was removed in vacuo and the residue was redissolved in ethyl acetate (50 ml), washed with sodium bicarbonate (50 ml) and dried (MgSO4). The solvent was removed in vacuo before the product was dissolved in dichloromethane (20 ml). The solution was cooled on an ice bath before di-isopropyl-ethyl amine (267 mg, 2.06 mmol) was added followed by drop wise addition of acetyl chloride (81 mg, 1.03 mmol) in dichloromethane (1 ml). The reaction mixture was stirred 1 hour at 0° C. before sodium bicarbonate (20 ml) was added. The mixture was extracted with dichloromethane (2×10 ml) and the combined organic fractions were dried (MgSO4). The crude product was purified by flash column chromatography (petrol ether/ethyl acetate (3:1)), which afforded 250 mg (46%) of 7-(S)-((acetyl-benzyl-amino)methyl)-2-amino-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
The title compound was obtained as a trifluoroacetate in a similar way as described in example 96 using the last three steps.
Oxalation: Standard procedure (54%)
Hydrogenolysis: Standard procedure (methanol-formic acid (10:1)) Yield 38 mg (26%)
Trifluoroacetic acid cleavage: Standard procedure 33 mg (80%)
LC-MS m/z: 432 [M+H]+, Rt=1.52 min
Calculated for C20H21N3O6S×1.5×C2HF3O2, 2×H2O C, 43.26%; H, 4.18%; N, 6.58%; Found: C, 43.19%; H, 3.86%; N, 6.46%.
Example 108




5-(S)-((1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of (S)-2-amino-5-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (1.0 g, 2.58 mmol) in dichloromethane (10 ml) at 0° C. was added N,N-diisopropylethylamine (0.54 ml, 5.16 mmol). A solution of 3-chloro-benzo[d]isothiazole 1,1-dioxide (0.52 g, 2.58 mmol) in dichloromethane (10 ml) was then added dropwise and stirred for 30 min. The solution was warmed to room temperature and washed with water and dried (MgSO4). The solvent was then removed in vacuo. The residue was taken into dichloromethane (15 ml) and imidazol-1-yl-oxo-acetic acid tert-butyl ester (1.0 g, 5.16 mmol) was added. The solution was stirred for 2 hours. The solvent was removed in vacuo. The residue was taken into ethyl acetate (100 ml). The solution was washed with 0.5 N hydrochloric acid solution, saturated sodium bicarbonate and brine, dried (MgSO4) and filtered. The solvent was removed in vacuo. The residue was chromatographed using a mixture of 0–5% ethyl acetate/dichloromethane as eluent, which afforded 0.6 g (34%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil
1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.94–7.92 (m, 1H), 7.79–7.71 (m, 2H), 7.59–7.50 (m, 1H), 7.38–7.27 (m, 4H), 6.86 (d, 1H, J=4 Hz), 4.14 (d, 1H, J=12 Hz), 3.95 (d, 1H, J=17 Hz), 3.88 (q, 1H, J=6 Hz), 3.70–3.62 (m, 1H), 3.47 (t, 1H, J=13 Hz), 3.34–3.24 (m, 1H), 3.06 (dd, 1H, J=17, 6 Hz), 2.53 (d, 1H, J=17 Hz), 1.62 (s, 9H), 1.61 (s, 9H), 1.44 (d, 3H, J=7 Hz).
A solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (252 mg, 0.37 mmol) in tetrahydrofuran (12 ml) was passed through Raney Ni (0.95 g, 50% Raney Ni-Water washed with methanol (6 ml) and tetrahydrofuran (10 ml) and dried before use). The solvent was removed in vacuo. The residue was dissolved in acetic acid (7 ml) and hydrogenated with 10% Pd/C (250 mg) at 50 psi for 15 hours. The mixture was filtered and the filtrate was added to saturated sodium bicarbonate solution. The solution was then extracted with ethylacetate (3×100 ml). The extracts were combined and dried (MgSO4). The solvent was removed in vacuo. The residue was washed with diethyl ether affording 156 mg (73%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)-methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3) δ 12.59 (s, 1H), 7.94–7.90 (m, 1H), 7.70–7.66 (m, 3H), 7.51 (s, 1H), 4.11 (d, 1H, J=12 Hz), 4.08 (q, 2H, J=17 Hz), 3.40 (dd, 1H, J=12, 6 Hz), 3.26–3.18 (m, 1H), 3.18 (d, 1H, J=17 Hz), 2.55 (dd, 1H, J=12, 6 Hz), 1.62 (s, 18H).
LC-MS: Rt=3.58 min, m/z: 577 [M+H]+.
A solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (149 mg, 0.26 mmol) in 50% trifluoroacetic acid/dichloromethane (1 ml) was left in an open flask for 60 hours. The volatiles were removed in vacuo and the residue was washed with dichloromethane to yield 80 mg (54%) of the title compound as a solid trifluoroacetate.
1H-NMR (DMSO-d6) δ 12.29 (s, 1H), 9.80 (s, 1H), 9.51 (bs, 2H), 8.19 (d, 1H, J=5 Hz), 8.02–8.00 (m, 1H), 7.89–7.84 (m, 2H), 4.46 (d, 1H, J=16 Hz), 4.30 (d, 1H, J=16 Hz), 3.96–3.80 (m, 3H), 3.30 (d, 1H, J=17 Hz), 2.93 (dd, 1H, J=18, 10 Hz);
LC-MS: Rt=0.68 min, m/z: 465[M+H]+.
Example 109




5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
The title compound was prepared in a similar way as described in Example 52 as a trifluoroacetate.
1H-NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.25 (bs, 2H), 7.80 (t, 1H, J=8 Hz), 7.59–7.32 (m, 7H), 5.37 (s, 2H), 4.42–4.21 (m, 2H), 3.95–3.70 (m, 3H), 3.4–3.2 (obscured by water, 1H), 2.83–2.75 (m, 1H)
LC-MS: Rt=2.16 min, m/z: 536.1 [M+H]+
Example 110




5-(6-Methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (57.4 mg, 0.142 mmol) and diisopropyl ethylamine (49 μl, 0.28 mmol) in acetonitrile (20 ml) at room temperature was added 2-bromomethyl-5-methoxy-isophthalic acid dimethyl ester (3.00 g, 7.45 mmol). The solution was stirred for 16 hours and the solvent evaporated in vacuo. The residue was taken into ethyl acetate (50 ml) and washed with water (2×20 ml), 1 N hydrochloric acid (20 ml), brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column using a mixture of ethyl acetate/hexane (1:1) as eluent, which afforded 62 mg (71%) of 2-amino-6-(4-methoxy-benzyl)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR δ (CDCl3): δ 7.75 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.11 (bs, 2H), 6.74 (d, 2H, J=8.0 Hz), 5.97 (s, 2H), 4.71 (d, 1H, J=18.4 Hz), 4.62 (d, 1H, J=18.4 Hz), 4.09 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.80 (m, 1H), 3.76 (s, 3H), 3.66–3.40 (m, 5H), 2.80 (d, 1H, J=17.2 Hz), 2.64 (d, 1H, J=17.2 Hz), 1.52 (s, 9H).
To a stirred solution of 2-amino-6-(4-methoxy-benzyl)-5-(6-methoxy-4-methoxy-carbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) in tetrahydrofuran (1.0 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (60 mg, 0.30 mmol) in tetrahydrofuran (1.0 ml). The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was taken into ethyl acetate (20 ml) and washed with 0.5 N hydrochloric acid (2×10 ml), saturated sodium bicarbonate (2×10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo and residue was chromatographed using a gradient ethyl acetate/hexane (10–25%) as eluent, which afforded 40 mg (58%) of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR δ (CDCl3): δ 12.54 (s, 1H), 7.75 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.10 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.0 Hz), 4.74 (d, 1H, J=18.4 Hz), 4.62 (d, 1H, J=18.4 Hz), 4.05–3.90 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.82–3.48 (m, 5H), 3.77 (s, 3H), 2.95 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 2.67 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 1.61 (s, 9H), 1.58 (s, 9H).
To a solution of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (38 mg, 0.055 mmol) in 10% formic acid/methanol (1.0 ml) at room temperature under nitrogen was added 10% Pd/C (38 mg). The mixture was stirred for 16 hours and the Pd/C was filtered off and the filtrate evaporated in vacuo. The residue was taken into dichloromethane (1.0 ml) poured into hexane. The precipitate was filtered off, affording 28 mg (82%) of 2-(tert-butoxyoxalyl-amino)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
1H-NMR δ (CDCl3): δ 12.45 (s, 1H), 10.90 (s, 1H), 10.69 (s, H), 7.73 (s, 1H), 7.42 (s, 1H), 4.85 (bs, 2H), 4.65 (bs, 1H), 4.42 (bs, 2H), 3.99 (bs, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 3.35 (bs, 1 Hz), 3.21 (bs, 1H), 1.62 (s, 9H), 1.56 (s, 9H).
To a solution of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was added 2-(tert-butoxyoxalyl-amino)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (14 mg, 0.023 mmol). The solution was stirred at room temperature for 40 hours. The reaction mixture was poured into diethyl ether (20 ml). The precipitate was filtered off, which afforded 10 mg (75%) of the title compound as a solid trifluoroacetate.
1H-NMR δ (DMSO-d6): δ 12.28 (s, 1H), 9.32 (s, 1H), 9.10 (s, 1H), 7.65 (d, 1H, J=2.4 Hz), 7.50 (d, 1H, J=2.4 Hz), 4.82 (d, 1H, J=17.2 Hz), 4.65 (d, 1H, J=17.6 Hz), 4.40 (d, 1H, J=17.6 Hz), 4.30 (m, 1H), 4.10 (dd, 1H, J=17.2 Hz and J=5.2 Hz), 3.95 (s, 1H), 3.89 (s, 6H), 3.85 (d, 1H, J=17.2 Hz), 2.81 (dd, 1H, J=18 Hz and J=7.2. Hz).
LC-MS: Rt=1.30 min; m/z: 504 [M+H]+
Example 111




2-(Oxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid and
2-(Oxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-aminomethyl-4-(2-spiro[1,3]dioxolane)-piperidine (193 mg, 1.12 mmol) and diisopropyl ethylamine (0.46 ml, 2.55 mmol) in acetonitrile (10 ml) cooled to 0° C. was added 2-chlorosulfonyl-benzoic acid methyl ester (278 mg. 1.18 mmol). The solution was stirred at 25° C. for 24 hours. Solvent was removed in vacuo and the residue was chromatographed using a mixture of ethyl acetate/hexane (1:3) as eluent, which afforded 199 mg (51%) of 2-(4-(2-spiro[1,3]dioxolane)piperidin-2-ylmethyl)-1,1-dioxo-1,2-dihydro-1H-benzo[d]isothiazol-3-one as a solid.
1H-NMR (CDCl3): δ 7.99–7.96 (m, 1H), 7.66–7.53 (m, 3H), 5.01 (s, 1H), 4.73 (dm, 1H, J=14.4 Hz), 4.06–3.93 (m, 6H), 3.25 (dd, 1H, J=12.6 Hz), 13.06 (td, 1H, J=13.5 Hz and J=3.6 Hz), 1.93 (dd, 1H, J=14.1 Hz and J=5.7 Hz), 1.87 (dd, 1H, J=14.1 Hz and J=3.0 Hz), 1.76 (dd, 1H, J=13.5 Hz and J=5.1 Hz).
LC-MS: Rt=1.78; m/z: 339 [M+H]+.
2-(4-(2-Spiro[1,3]dioxolane)piperidin-2-ylmethyl)-1,1-dioxo-1,2-dihydro-1H-benzo[d]isothiazol-3-one (199 mg, 0.588 mmol) was dissolved in 2 M hydrochloric acid (12 ml) and the solution was heated to 50° C. for 24 hours. The volatiles were removed in vacuo and the residue (341 mg) was treated without further purification with saturated sodium carbonate (12 ml), dichloromethane (8 ml) and di-t-butyl-dicarbonate (1.64 g, 7.5 mmol). The mixture was stirred at 35° C. for 3 days and extracted with dichloromethane (30 ml). The organic solution was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column using a mixture of ethyl acetate/hexane (1:3) as eluent, which afforded 115 mg (50%) of 4-oxo-2-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester as an oil.
1H-NMR (CDCl3): δ 8.06 (dd, 1H, J=6.0, 1.8 Hz), 7.95–7.80 (m, 3H), 5.02 (bs, 1H), 4.35 (bs, 1H), 3.91 (dd, 1H, J=15.0 Hz and J=8.4 Hz), 3.78 (dd, 1H, J=14.7 Hz and J=5.7 Hz), 3.53 (t, 1H, J=10.8 Hz), 2.74 (dd, 1H, J=15.0 Hz and J=7.5 Hz), 2.60–2.38 (m, 3H), 1.32 (s, 9H).
To a solution of 4-oxo-2-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (115 mg, 0.292 mmol) in absolute ethanol (5 ml) was added t-butyl cyanoacetate (57 μl, 0.41 mmol), sulfur (13 mg, 0.41 mmol) and morpholine (55 μl, 0.63 mmol). The solution was stirred at 50° C. for 14 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel column using a mixture of ethyl acetate/hexane (1:4) as eluent, which afforded 100 mg (62%) of 2-amino-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-amino-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a mixture.
1H-NMR (CDCl3): δ 8.10–8.00 (r, 1H), 7.98–7.77 (m, 2.8H), 7.66–7.58 (m, 0.2H), 6.11 (s, 0.4H), 6.06 (s, 0.6H), 5.59 (m, 0.2H), 5.39 (t, 0.3H, J=5.7 Hz) 5.23 (bs 0.3H), 5.04 (bs, 0.4H), 4.77 (d, 0.4H, J=14.4 Hz), 4.60 (d, 0.4H, J=14.4 Hz), 4.45–4.18 (m, 1H), 4.02–3.82 (m, 1.5H), 3.64 (dd, 0.5H, J=14.7 Hz and J=5.2 Hz), 3.30–2.60 (m, 2H), 1.54 (s, 7H), 1.53 (s, 2H), 1.26 (s, 7H), 1.21 (s, 2H).
To a stirred solution of the above 2-amino-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-amino-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester mixture (100 mg, 0.18 mmol) in acetonitrile (7 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (290 mg, 1.46 mmol) in acetonitrile (1 ml). The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken into ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution, saturated sodium bicarbonate, brine, dried MgSO4) and filtered. The solvent was removed in vacuo and the residue was chromatographed on silicagel using a mixture of ethyl acetate/hexane (1:4) as eluent, which provided 98 mg (80%) of a mixture of 2-(tert-butoxyoxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-(tert-butoxyoxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
1H-NMR (CDCl3): δ 12.60 (s, 0.3H), 12.54 (s, 0.7H), 8.12–8.06 (m, 1H), 7.98–7.80 (m, 2.8H), 7.66–7.58 (m, 0.2H), 5.83 (bs, 0.1H), 5.61 (t, 0.2H), 5.40–4.54 (m, 0.9H), 4.53–4.40 (m, 0.8H), 4.02–3.70 (m, 1.42H), 3.66 (dd, 0.58H, J=14.7 Hz and J=5.2 Hz), 3.30–2.99 (m, 3H), 1.68 (s, 6H), 1.62 (s, 6H), 1.60 (s, 6H), 1.31 (s, 4.5H), 1.25 (s, 4.5H);
LC-MS: Rt 4.45; m/z: 678 [M+H]+.
To a solution of trifluoroacetic acid (4 ml) and dichloromethane (2 ml) was added the mixture of 2-(tert-butoxyoxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-(tert-butoxyoxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (78 mg, 0.12 mmol). The solution was stirred at room temperature for 24 hours. The solvent was then evaporated in vacuo, which afforded 50 mg (72%) of the title compounds as a mixture of trifluoroacetates.
1H-NMR (DMSO-d6): δ 12.32 (s, 1H), 9.75–9.20 (m, 2H), 8.40 (t, 1H, J=6.0 Hz), 8.22–8.02 (m, 3H), 5.03 (bs, 0.5H), 4.52 (d, 1H), 4.38–4.10 (m, 2H), 3.88 (bs, 0.5H), 3.70–3.64 (m, 0.5H), 3.44–3.34 (m, 0.5H), 3.20–2.90 (m, 2H).
LC-MS: Rt=1.28 min, m/z: 466 [M+H]+
Example 112




7-(R)-Carbamoyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-(S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert butyl ester (18.4 g, 75.6 mmol) and triethylamine (12.65 mL, 90.79 mmol) in tetrahydrofuran (50 mL) cooled to −20° C. was added isobutylchloroformate (11.81 mL, 90.79 mmol) and the mixture was stirred for 10 min at −20° C. before a 25% solution of ammonia in water (100 mL) was added. The temperature was kept at −20° C. for 30 min before the cooling bath was removed and the reaction mixture was allowed to reach room temperature and stirring was continued for another hour. The reaction mixture was extracted with ethyl acetate (6×50 mL) and the combined organic phases were dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, Flash 40, ethyl acetate) to give 8.51 g (46%) of 2-(S)-carbamoyl-4-oxo-piperidine-1-carboxylic acid 1-tert-butyl ester.
A solution of 2-(S)-carbamoyl-4-oxo-piperidine-1-carboxylic acid 1-tert butyl ester (3.51 g 14.48 mmol), tert-butyl cyanoacetate (2.04 g, 14.48 mmol), sulphur (0.464 g, 14.48 mmol) and diisopropyl ethylamine (2.5 mL, 14.48 mmol) in methanol (20 mL) was heated 16 hours at 40° C. under N2. The volatiles were removed in vacuo and the residue was purified using column chromatography (SiO2, Flash 40, petroleum ether/ethyl acetate 3:1) to give 1.33 g (23%) of a mixture 2-amino-5-(S)-carbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-di-carboxylic acid di-tert-butyl ester and 2-amino-7-(R)-carbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-di-carboxylic acid di-tert-butyl ester isomers.
0.5 g (1.25 mmol) of the above mixture was dissolved dichloromethane (10 mL) and imidazole-1-yl-oxo-acetic acid tert-butyl ester (0.74 g, 3.77 mmol) and triethylamine (0.525 mL, 3.77 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature before the volatiles were removed in vacuo. The residue was purified by column chromatography (SiO2, Flash 40, petroleum ether/ethyl acetate (4:1)) too give 75 mg (11%) of 2-(tert-butoxyoxalyl-amino)-7-(R)-carbamoyl-4,7-dithydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester. This was dissolved in a mixture of trifluoacetic acid/dichloromethane (1:1) (10 mL) and stirred for 16 hours at room temperature before the solvent was removed in vacuo. The residue was recrystallized from methanol to give 24 mg (39%) of the title compound.
LC-MS; Rt=1.56 min, m/z: 314 [M+H]+
Calculated for C11H11N3O6S, 0.25×C2HF3O2, 0.75×H2O C, 38.88%; H, 3.62%; N, 11.83%; Found: C, 38.92%; H, 3.92%; N, 11.81%.
Example 113




2-(Oxalyl-amino)-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,5-(S),6-tri-carboxylic acid 3,6-di-tert-butyl ester (0.30 g, 0.75 mmol) and triethylamine (0.21 mL, 1.51 mmol) in tetrahydrofuran (10 mL) was cooled to −20° C. before isobutyl chloroformate (0.103 mL, 0.75 mmol) was added. The reaction mixture was stirred 15 min at −20° C. before homocystein hydrochloride (116 mg, 0.75 mmol) was added. The cooling bath was removed and the reaction mixture was left for 16 hours at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography (SiO2, Flash 40, heptane/ethyl acetate 2:1) to give 212 mg (56%) of 2-amino-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester
A solution of 2-amino-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (200 mg, 0.40 mmol), imidazole-1-yl-oxo-acetic acid tert-butyl ester (235 mg, 1.20 mmol) and triethylamine (168 μL, 1.20 mmol) in dichloromethane (10 mL) was stirred for 16 hours at room temperature before the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, Flash 40, heptane/ethyl acetate 2:1) to give 250 mg (100%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester.
This was dissolved in a mixture of trifluoroacetic acid/dichloromethane (1:1) (3 mL) and stirred for 16 hours at room temperature before diethyl ether (6 mL) was added. The precipitate was filtered off and washed with diethyl ether to give 172 mg (81%) of the title compound as a solid trifluoroacetate.
LC-MS; Rt=0.41 min, m/z: 414 [M+H]+
Calculated for C15H15N3O7S2, 1.5×C2HF3O2, H2O; C, 35.88%; H, 3.10%; N, 6.97%; Found: C, 35.91%; H, 3.54%; N, 6.97%.
Example 114




2-(Oxalyl-amino)-5-(S)-phenylcarbamoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
A solution of 2-amino-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3,5-(S),6-tricarboxylic acid 3,5-di-tert-butyl ester (300 mg, 0.75 mmol) and triethylamine (210 μL, 1.51 mmol) in tetrahydrofuran (10 mL) was cooled to −20° C. before isobutylchloroformate (103 mg, 0.75 mmol) was introduced. The reaction mixture was stirred for 20 min before aniline (70 mg, 0.75 mmol) was added. The cooling bath was removed and the reaction was left for 16 hours at room temperature before the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (10 mL) and imidazole-1-yl-oxo-acetic acid tert-butyl ester (443 mg, 2.26 mmol) and triethylamine (315 μL, 2.26 mmol) was added. The reaction mixture was stirred 16 hours at room temperature before the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, Flash 40, heptane/ethyl acetate (3:1) to give 250 mg 2-(tert-butoxyoxalyl-amino)-5-(S)-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester.
2-(tert-Butoxyoxalyl-amino)-5-(S)-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester was dissolved in a mixture of trifluoroacetic acid/dichloromethane (1:1) (3 mL) and stirred for 16 hours at room temperature before diethyl ether (6 mL) was added. The precipitate was filtered off and washed with diethyl ether to give 155 mg (41%) of the title compound as a solid trifluoroacetate.
LC-MS; Rt=0.86 min, m/z: 390 [M+H]+
Calculated for C17H15N3O6S, 1.5×C2HF3O2, H2O; C, 41.53%; H, 3.22%; N, 7.26%; Found: C, 41.77%; H, 3.29%; N, 7.28%.
Example 115




2-(Oxalyl-amino)-7-(R)-phenylcarbamoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
To a solution of 2-(S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert butyl ester (2.06 g, 8.47 mmol) and triethylamine (1.42 mL, 10.16 mmol) in tetrahydrofuran (20 mL) cooled to −20° C. was added isobutylchloroformate (1.39 g, 10.16 mmol) and the mixture was stirred for 10 min at −20° C. before aniline (946 mg, 10.16 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 16 hours at room temperature before the solvent was removed in vacuo. The residue was divided between water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride (25 mL) and dried (MgSO4). After filtration and concentration in vacuo the residue was purified using column chromatography (SiO2, Flash 40, petroleum ether/ethyl acetate 5:1) to give 1.3 g (48%) of 4-oxo-2-(S)-phenyl-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester.
A solution of 4-oxo-2-(S)-phenylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.3, 4.08 mmol), tert-butylcyanoacetate (0.58 g, 4.08 mmol), sulphur (0.133 g, 4.08 mmol) and diisopropyl ethylamine (0.7 mL, 4.08 mmol) in methanol (10 mL) was heated under nitrogen to 40° C. for 16 hours before the solvent was removed in vacuo. The residue was subjected to column chromatography (SiO2, Flash 40, petroleum ether/ethyl acetate 6:1) to give 0.70 g (36%) of a mixture of 2-amino-5-(S)-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-di-carboxylic acid di-tert-butyl ester and 2-amino-7-(R)-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-di-carboxylic acid di-tert-butyl ester isomers. The above mixture was dissolved in dichloromethane (20 mL) and imidazole-1-yl-oxo-acetic acid tert-butyl ester (872 mg, 4.44 mmol) and triethylamine (618 μL, 4.44 mmol) was added. The reaction mixture was stirred 16 hours before the solvent was removed in vacuo and the residue was subjected to column chromatography (SiO2, Flash 40, petroleum ether/ethyl acetate 5:1) to give 0.50 g (56%) as a mixture of 2-(tert-butoxyoxalyl-amino)-5-(S)-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-di-carboxylic acid di-tert-butyl ester and 2-(tert-butoxyoxalyl-amino)-7-(R)-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-di-carboxylic acid di-tert-butyl ester
300 mg of the mixture was dissolved in a mixture of trifluoacetic acid/dichloro-methane (1:1) (6.0 mL) and the solution was stirred for 16 hours at room temperature before the solvent was removed in vacuo. The residue was purified on preparative HPLC to give 70 mg (34%) of the title compound as a solid trifluoroacetate.
LC-MS; Rt=0.95 min, m/z: 390 [M+H]+
Calculated for C17H15N3O6S, C2HF3O2, H2O; C, 43.77%; H, 3.48%; N, 8.06%; Found: C, 43.92%; H, 3.44%; N, 7.97%.
Example 116




5-(R),7-(R)-Bis-benzyloxymethyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
Benzyloxyacetaldehyde (0.90 g; 6.0 mmol) and dimethyl(2-oxomethyl)phosphonate (1.0 g; 6.0 mmol) were dissolved in a mixture of tetrahydrofuran (25 ml) and water (20 ml). 1N Aqueous potassium hydroxide (6 ml) was added and the mixture was stirred for 30 min. Dichloromethane (50 ml) was added and the organic phase was separated, dried (MgSO4) and evaporated in vacuo leaving 5-benzyloxypent-3-en-2-one.
1H-NMR: 2.25 (s, 3H); 4.19 (dd, 2H); 4.55 (s, 2H); 6.34 (dt; 1H); 6.70 (dt, 1H); 7.26 (m, 5H).
5-benzyloxypent-3-en-2-one was dissolved in methanol (5 ml) and ammonium acetate (13 mmol, 1.03 g) was mixted together with benzyloxyacetaldehyde (1.8 g; 12 mmol) and acetic acid (0.69 ml) and the mixture was stirred for 2 days. The solvent was removed in vacuo and the residue was chromatographed on silica using gradient elution from 100% dichloromethane to 100% ethyl acetate. A fraction (411 mg) contained (according to LC-MS; m/z 340.4) 2,5-di(benzyloxymethyl)-4-piperidone in an impure state was isolated. The crude mixture was dissolved in ethanol (3 ml) and tert-butylcyanoacetate (400 mg), sulfur (100 mg) and triethylamine was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on silica in a mixture of dichloromethane/(7% of 25% aqueous ammonia in ethanol) (40:1), which afforded 0.14 g of 2-amino-5-(R),7-(R)-bis-benzyloxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
LC-MS: Rt: 6.03 min; m/z: 495.2 [M+H]+
2-amino-5-(R),7-(R)-Bis-benzyloxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.14 g; 0.28 mmol) was dissolved in dichloromethane (5 ml) and treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.1 g; 0.5 mmol) and triethylamine (70 μl; 0.5 mmol), and stirred overnight, washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed on silica using ethyl acetate/dichloromethane (1:3) as eluent. The residue was treated with trifluoroacetic acid (0.5 ml) in dichloromethane (0.5 ml) and stirred for 4 hours. Evaporation of the solvent in vacuo afforded 37 mg of the title compound.
LC-MS: Rt: 4.74 min; m/z: 511.4 [M+H]+.
Example 117




6-Benzyl-2-(oxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
1-Benzyl-4-oxo-piperidine-2-carboxylic acid ethyl ester (2.9 g; 11.1 mmol) (prepared in a similar way as described in “GENERAL CHIRAL SYNTHESIS” for 4-oxo-1-((S)-1-phenyl-ethyl)-piperidine-(R)-2-carboxylic acid ethyl ester using benzylamine instead of 1-(S)-phenethylamine) was dissolved in abs. ethanol (50 ml) and sulfur (0.35 g, 11.1 mmol), triethylamine (1.6 ml, 11.1 mmol), and tert-butylcyanoacetate (1.7 g, 11.1 mmol) were added and the mixture was stirred 2 days at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica using a mixture of ethyl actetate/heptane (1:4) as eleuent leaving a mixture (700 mg; 1:1 based on NMR) of 2-amino-6-benzyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,7-dicarboxylic acid 3-tert-butyl ester-7-ethyl ester and 2-amino-6-benzyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,7-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester which was used in the next step without separation. To this mixture was added tetrahydrofuran (5 ml) and lithium borohydride (1.1 ml of a 2M solution in tetrahydrofuran) and the mixture was stirred 18 hours. More lithium borohydride (5.0 ml of a 2M solution in tetrahydrofuran) was added and the mixture stirred for an additiona 4 days. Ethyl acetate (10 ml) was added dropwise and after 1 hour the mixture was poured onto water (100 ml) and extracted with dichloromethane (2×100 ml) and chromatographed on silica (using ethylacetate/heptane 1:1 as eluent), which afforded a mixture of 2-amino-6-benzyl-7-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester and 2-amino-6-benzyl-5-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (in total 187 mg). To this mixture was added dry tetrahydrofuran (10 ml), 2,3-dihydro-1,2-benzisothiazol-3-one-1,1-dioxide (100 mg; 0.55 mmol), triphenylphosphine (144 mg 0.55 mmol) and the mixture was cooled with ice. Diethyl azodicarboxylate (86 μl) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue was chromatographed on silica using a mixture of ethyl acetate/heptane (1:1) as eluent leaving 94 mg of 2-amino-6-benzyl-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
1H-NMR: (CDCl3): 1.52 (s, 9H); 2.75 (dd, 1H); 2.90 (dd, 1H); 3.55 (d, 1H); 3.72 (m, 4H); 3.94 (d, 1H); 4.12 (d, 1H); 5.97 (s, 2H); 7.14–7.37 (m, 5H); 7.80–8.03 (m, 4H).
LC-MS: Rt 5.47 min, m/z: 540.4 [M+H]+
2-Amino-6-benzyl-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (94 mg; 0.17 mmol) was dissolved in dichloromethane (5 ml) and treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.07 g; 0.3 mmol) and triethylamine (49 μl; 0.3 mmol), and stirred overnight, washed with water, 1N aqueous citric acid, dried (MgSO4) and the solvent removed in vacuo leaving 104 mg of 2-(tert-butoxyoxalyl-amino)-6-benzyl-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
LC-MS: Rt: 5.50 min, m/z: 668.6 [M+H]+
2-(tert-Butoxyoxalyl-amino)-6-benzyl-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (100 mg; 0.15 mmol) was treated with trifluoroacetic acid (1 m) in dichloromethane (4 ml) and stirred for 2 days. Evaporation of the solvent in vacuo afforded 90 mg of the title compound as a solid trifluoroacetate.
Calc. for C25H21N3O8S2, 1.5×C2HF3O2, 0.5×H2O C, 45.72%; H, 3.22%; N, 5.71%. Found: C, 45.48%; H, 3.46%; N, 5.72%
LC-MS: Rt: 4.16 min; m/z: 556.2 [M+H]+
Example 118
Crystallisation of Protein and Protein-Inhibitor Complexes
Co-Crystallization of PTP1B with Inhibitors;
A 6–10 mg/ml preparation of PTP1B in 10 mM Tris pH 7.5, 25 mM NaCl, 0.2 mM EDTA and 3 mM DTT, was used for crystallization. Crystals were grown by the sitting as well as the hanging drop vapor diffusion methods. A 1:10 (PTP1B:inhibitor) molar ratio mixture was prepared at least one hour prior to crystallization. Two μl of PTP1B-inhibitor solution was mixed with 2 μl reservoir solution consisting of: 0.1 M Hepes buffer pH 7.5, 0.3–0.4 M Na-acetate or Mg-acetate, 12–16% Peg 8000 and/or 4% glycerol. The reservoir volume was 1 ml. Crystals grew to the size of 0.3–0.6×0.1–0.3×0.1–0.3 mm over 2–3 days.
Data Collection.
All crystal data collections were performed at 100 K. The following cryo conditions were used: to the hanging or sitting drop 3 μl of 50% glycerol (containing 0.5 mmol inhibitor) were added. The crystal was removed from the drop after 5–30 min. and transferred to 50% glycerol (containing 0.5 mmol inhibitor) and rapidly flash frozen.
Data were collected using a mar345 image plate either at the MAX-lab synchrotron facilities in Lund (Sweden) or in-house equipped with a rotating anode (RU300) and Osmic multilayer mirror system. Typically a 1° oscillation was used for 60 images data sets in the resolution range 2.7–1.8 Å were obtained. The space group was determined to be P3121 for all crystals used.
Refinements.
As P3121 contains a polar axis and, thus, possesses more than one indexing possibility, a molecular replacement solution using Amore [ref] solution was found prior to the refinements. A high resolution PTP1B structure was used as a starting model, with ligand and water molecules omitted from the structure. All refinements were performed with Xplor. v. 3.851 [MSI]. Interchanging cycles of model building using X-build [MSI] and refinement were performed. The 2Fo-Fc maps were inspected by the use of X-ligand [MSI] at a 1.3 sigma level for densities that could correspond to the structures of the inhibitors. In all cases a well-suited inhibitor electron density was identified in the active site pocket, see FIGS. 1–4. No other densities were identified to fit the inhibitors. Water molecules were inserted using the X-solvate program [MSI].
Example 119
Coupling of 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid to Epoxy-activated Sepharose 6B
This example describes the preparation of an immobilized compound suited for affinity chromatographic purification of PTPases (eg PTP1B or T-cell PTP).
3.5 g Epoxy-activated Sepharose 6B (Pharmacia Biotech) was prepared for coupling according to the manufacturers directions, and divided into 3 portions (3×8 ml gel-suspension, corresponding to 4 ml drained gel each).
8 ml portions of 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid dissolved to 10, 1 and 0.1 mM in a 0.2 M sodium carbonate coupling buffer pH 9 were mixed with the gel suspensions and agitated gently overnight at room temperature.
Exces ligand was washed away, the remaining active groups were blocked and the product was washed extensively at alternating pH, all according to the the manufacturers directions.
The products were stored refrigerated in 0.1 M acetate pH 4.0 containing 0.5 M sodium chloride.
Significant inhibition of PTP1B was demonstrated in the 20 μmole ligand/ml gel preparation, when diluted to 1 μl drained gel/ml.
Example 120
Affinity purification of PTP1B using the compound 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid coupled to Epoxy-activated Sepharose 6B
This example describes the affinity chromatographic purification of a PTPase.
2 ml of the product with 20 μmole ligand/ml described in example 55 was loaded into a 1.6 cm diameter column and equilibrated with a buffer (buffer A) containing
20 mM L-histidine
1 mM EDTA
7 mM Mercaptoethanol
100 mM Sodium chloride
and adjusted to pH 6.2 with 1 M HCl.
1.5 mg conventionally purified PTP1B in 5 ml buffer A, was applied to the column at 0.5 ml/min followed by a wash with 10 ml buffer A.
UV absorbing material without PTPase activity, corresponding to approx. 10% of the totally applied material, passed through the column.
The flow direction was reversed, the flow increased to 2 ml/min and linear gradient elution started with a combined salt and pH gradient for 20 minutes using buffer B containing
20 mM L-histidine
1 mM EDTA
7 mM Mercaptoethanol
1 M Sodium chloride
and adjusted to pH 9.0 with 1 M NaOH.
Maximum elution took place at approx. 32% buffer B (0.39 M NaCl and pH 6.8) in a broad peak.
The total activity yield in the elution peak was 70%, and the specific activity of the enzyme was improved by a factor 1.4.
Example 121
Use of Compounds of the Invention to Identify Substrates that Are Specifically Dephosphorylated by PTPases that Are Inhibited by the Compounds of the Invention or by Other PTPases
The compounds of the invention are unique tools for identification of cellular substrates of the PTPases that are inhibited by the compounds of the invention. Substrates are herein defined as cellular proteins that (i) are phosphorylated on tyrosine residues, (ii) are dephosphorylated by PTPases that are inhibited by compounds of the invention or by other PTPases. If said substrates are dephosphorylated by PTPases that are inhibited by compounds of the invention, administration of the compounds of the invention will result in partial or total prevention of dephosphorylation of said substrates. As a result, a concomitant prolonged or increased activation may be observed of the signal transduction pathway (for definition, vide infra) in which said substrate is involved. Non-limiting examples of substrates are: the insulin receptor β subunit, IRS-1, IRS-2, IRS-3, IRS-4, JAK1, JAK2, shc-2, grb-2 (Hunter, Cell 100:113–127 (2000)).
Importantly, the compounds of the invention can also be used to identify novel substrates. When the compounds of the invention have been used to identify the substrates of the PTPases that are inhibited by the compounds of the invention, a person skilled in the arts will be able to use this knowledge to establish animal models that will reflect a human condition or disease in which a compound of the invention will be indicated. Non-limiting example of the usefulness of said compounds of the invention will be in the following disease areas: diabetes, obesity cancer and conditions with unwarranted platelet aggregation.
To identify the substrates of the PTPases that are inhibited by the substrates of the invention the following methods may be employed. Whole animals and/or primary cells and/or cell lines that represent the target organ or tissue may be used for these experiments. Non-limiting examples of animals are: ob/ob mice (worldwide web @ jax.org); db/db mice; Zucker obese rats. Non-limiting examples of target tissues or organs are: skeletal muscle, liver, adipose tissue, pancreas, the spleen, the bone marrow. Non-limiting examples of cell lines are: Chinese hamster ovary (CHO) cells (CHO-K1—American Type Culture Collection (ATCC) Number CCL-61), Baby Hamster Kidney (BHK) cells (ATCC Number CRL-1632), HepG2 cells (ATCC Number HB-8065), C2C12 cells (ATCC Number CRL-1772), L6 cells (ATCC Number CRL-1458), RD cells (ATCC Number CCL-136). Said cells can either be unmanipulated or transfected transiently or permanently with plasmid vectors that encode proteins or substrates. Non-limiting example of a plasmid that allows expression in mammalian cells are: pcDNA1 and pcDNA3 (worldwode web @ invitrogen.com). Non-limiting examples of proteins or substrates that are transfected into said cell lines are: the insulin receptor, the IGF-I receptor, the EGF-R receptor; the PDGF receptor, IRS-1, IRS-2, IRS-3, IRS-4, p56Lck; Jak1, Jak2 (Hunter, supra).
The analysis consists of the following steps:
(A) stimulation of signal transduction pathways with and without the presence of the compounds of the invention. Signal transduction pathways are herein defined as a series of cellular processes that are initiated by a triggering event (such as stimulation of a tissue or cell by a hormone and/or a cytokine and/or cell—cell interaction and/or cell—cell substratum interaction) leading to various cellular effects including metabolic effects, cell differentiation and cell proliferation (Hunter, supra). Non-limiting examples of signal transduction pathways include: the insulin signaling pathway; the leptin signalling pathway; thrombin signalling pathway; the erythropoietin signaling pathway; the epidermal growth factor signaling pathway. Non-limiting examples of the effects of stimulating signal transduction pathways: glucose uptake; glycogen synthesis; cell proliferation; cell differentiation; platelet aggregation.

(B) Analysis and identification of substrates that show increased (or decreased) phosphorylation on tyrosine residues after administration of the compound of the invention in comparison with controls that did not receive the compound.

Step A. Stimulation of Signal Transduction Pathways.

As a non-limiting example, insulin (concentration range: 0.1 to 100 nM, final concentration) is administered to primary hepatocytes in tissue culture plates. The compounds of the invention (concentration range: 10 nM to 100 μM) are administered to half of the plates, with the other plates acting as controls. The plates are incubated at 37° C. for various time periods: Typically for 0, 1, 2, 5, 15, 30 and 60 mins. Following this stimulation, the plates are treated as follows: The medium is rapidly aspirated and the cells washed twice with ice-cold PBS. Two milliliters of ice-cold lysis buffer (see below) is added and the plates are placed on ice for 2 minutes after which the cells are scraped off using a cell scraper (‘rubber policeman’). The lysates are placed at 4° C. at a rotary shakerr. Dithiotreitol is added to a final concentration of 10 mM, and the lysates are centrifuged at 20,000 r.p.m. Aliquots of the supernatants, i.e. lysates, are stored at −80° C. until further use.
Lysis buffer—for a total of 20 ml add the following
0.8 ml of 500 mM Tris-Cl, pH 7.4
0.2 ml of 100 mM EDTA
2.0 ml of 1 M NaCl
2.0 ml of 10% (vol/vol) Triton X-100
80 μl of 250 mM PMSF
2 μl of 10 mg/ml aprotinin
20 μl of 1 mg/ml leupeptin
5 mM 100 mM iodoacetate
11.88 ml demineralized water
Step B. Analysis and Identification of Substrates that Show Increased (or Decreased) Phosphorylation on Tyrosine Residues after Administration of the Compound of the Invention in Comparison with Controls that Did not Receive the Compound.
As a non-limiting example, said lysates are subjected to two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) followed by detection of proteins that are phosphorylated on tyrosine residues (pTyr) by western blotting, techniques well-known to those skilled in the art (Marcus et al. Electrophoresis 21: 2622–2636 (2000)). Proteins that show increased (or decreased) pTyr are identified by comparing the western blots made from said lysates derived from said hepatocytes treated with both insulin and the compounds of the invention with said control lysates derived from said hepatocytes that were treated with insulin only. Increased pTyr of a protein shows that the said protein is regulated by the PTPase or PTPases that are inhibited by the compounds of the invention. Said protein may either be a direct substrate of the PTPase or PTPases that are inhibited by the compounds of the invention or the substrate of other PTPase(s) which activity is regulated by the PTPase or PTPases that are inhibited by the compounds of the invention. Decreased pTyr of a protein shows that said protein is the substrate of other PTPase(s) that is/are activated, directly or indirectly, by the PTPase or PTPases that are inhibited by the compounds of the invention. Having identified and visualized proteins, i.e. substrates, that show changed pTyr levels, the spots are cut out, digested with trypsin and analyzed by matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) (Marcus et al., supra). To identify the nature of said substrate with changed pTyr levels the obtained mass fingerprints are analyzed as described by Marcus et al. (supra) or other methods well-known to those skilled in the art.
Said substrate can either be an already described protein or a novel protein. In both cases, the identification may be followed by cDNA cloning procedures with the aim of obtaining a full-length clone corresponding to said substrate using standard techniques well-known to those skilled in the art (Ausubel, F. M., et al. (ED.). Short Protocols in Molecular Biology, 2nd ed, John Wiley and Sons, inc., New York, ISBN0-471-57735-9 (1992)). Said full-length clone may be expressed as recombinant proteins in prokaryotic or eukaryotic expression systems well-known to those skilled in the art (worldwide web @ invitrogen.com; worldwide web @ stratagene.com; worldwide web @ promega.com), and the function of said substrate may in turn be studied both at the biochemical and cellular levels. Further, said recombinant proteins may further be used as an antigen to produce either polyclonal or monoclonal antibodies using techniques well-known to those skilled in the art. As a non-limiting example, with said full-length clone, said antibodies, and the compounds of the invention at hand, those skilled in the art will be able to study the tissue distribution and expression levels of said substrates in normal animals and animal models of diseases, such as diabetes, obesity, cancer and disturbances of platelet aggregation. A person skilled in the art will be able to use this knowledge to establish animal models or use already established animal models that will reflect a human condition or disease in which a compound of the invention will be indicated. Non-limiting example of the usefulness of said compounds of the invention will be in the following disease areas: diabetes, obesity, cancer and conditions with unwarranted platelet aggregation.
Example 122
Identification of Substrates that are Dephosphorylated by PTPases that are Inhibited by the Compounds of the Invention
The analysis consists of the following steps: (A) preparation of hyperphosphorylated substrates; (B) identification of said substrates that are dephosphorylated by PTPases that are dephosphorylated by compounds of the invention.
To identify the substrates of the PTPases that are inhibited by the compounds of the invention the following method may be employed. Primary cells and/or cell lines that represent the target organ or tissue may be used for these experiments. Non-limiting examples of target tissues or organs are: skeletal muscle, liver, adipose tissue, pancreas, the spleen, the bone marrow. Non-limiting examples of cell lines are: Chinese hamster ovary (CHO) cells (CHO-K1—American Type Culture Collection (ATCC) Number CCL-61), Baby Hamster Kidney (BHK) cells (ATCC Number CRL-1632), HepG2 cells (ATCC Number HB-8065), C2C12 cells (ATCC Number CRL-1772), L6 cells (ATCC Number CRL-1458), RD cells (ATCC Number CCL-136). Said cells can either be unmanipulated or transfected transiently or permanently with plasmid vectors that encode proteins or substrates. Non-limiting example of a plasmids that allow expression in mammalian cells are: pcDNA1 and pcDNA3 (worldwide web @ invitrogen.com). Non-limiting examples of proteins or substrates that are transfected into said cell lines are: the insulin receptor, the IGF-I receptor, the EGF-R receptor, the PDGF receptor, IRS-1, IRS-2, IRS-3, IRS-4, p56Lck; Jak1, Jak2 (Hunter, supra).
Step A
Said primary cells, tissues or cell lines are exposed to a general inhibitor of PTPases. This treatment results in induction of hyperphosphorylation of a multitude of cellular substrates. A non-limiting example of a general PTPase inhibitor is bisperoxovanadium 1,10 phenanthroline (bpV(phen)) (Posner et al. J. Biol. Chem. 269: 4596–4604 (1994)).
A non-limiting example of a hyperphosphorylation protocol: CHO cells that stably overexpress the insulin receptor are grown in 15 cm Petri dishes to 80–90 percent confluence (using F-12 medium with 10 percent fetal calf serum). The culture medium is replaced with medium that does not contain calf serum and are grown for additional 2 hrs at 37° C. The plates are washed twice with phosphate buffered saline (PBS) and incubated for further 2 hours with 100 μM bpV(phen) and 100 nM insulin (Novo Nordisk) (final assay concentrations). Following this stimulation the plates are treated as follows: The medium is rapidly aspirated and the cells washed twice with ice-cold PBS. Two milliliters of ice-cold lysis buffer (see below) is added and the plates are placed on ice for 2 minutes after which the cells are scraped off using a cell scraper (‘rubber policeman’). The lysates are placed at 4° C. at a rotary shaker for 1 hour. Dithiotreitol is added to a final concentration of 10 mM, and the lysates are centrifuged for 10 minutes at 20,000 r.p.m. Aliquots of the supernatants, i.e. lysates, are stored at −80° C. until further use.
Lysis buffer—for a total of 20 ml add the following:
0.8 ml of 500 mM Tris-Cl, pH 7.4
0.2 ml of 100 mM EDTA
2.0 ml of 1 M NaCl
2.0 ml of 10% (vol/vol) Triton X-100
80 μl of 250 mM PMSF
2 μl of 10 mg/ml aprotinin
20 μl of 1 mg/ml leupeptin
5 mM 100 mM iodoacetate
11.88 ml demineralized water
Step B
For these studies both novel and known PTPases may be used. The PTPases may be either isolated using the compounds of the invention as described in Example 120 or recombinant proteins. Non-limiting examples of known PTPases that are inhibited by compounds of the invention are PTP1B and TC-PTP. The cDNA for these PTPases are inserted in prokaryotic expression vectors and are expressed in E. coli. An overnight culture is diluted 1:25 into a total volume of 2 liters of SOB medium and grown at 37° C. for 3 hours. Isopropyl β-D-thiogalactoside (IPTG) is added to a final concentration of 0.1 mM, and the incubation is continued at room temperature for 3 hrs. The fusion proteins are purified according to the manufacturer's instructions (Amersham Pharmacia Biotech).
Aliquots of said lysates (60 μl) are mixed with said PTPase that is inhibited by said compound of the invention and incubated on ice for 1, 10, and 30 minutes. At each time point, 20 μl aliquots are removed and mixed with SDS loading buffer (20% (v/v) glycerol, 3% (w/v) SDS, 3% (v/v) 2-mercaptoethanol, 10 mM EDTA, 0.05% (w/v) bromophenol blue), heated at 100° C. for 2 minutes and stored at −20° C. until use. Control lysates without addition of PTPase are treated identically.
As a non-limiting example, said lysates are subjected to two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) followed by detection of proteins that are phosphorylated on tyrosine residue (pTyr) by western blotting, techniques well-known to those skilled in the art (Marcus et al. Electrophoresis 21: 2622–2636 (2000)). Proteins that show decreased pTyr are identified by comparing the western blots made from said lysates treated with said PTPase with said control lysates. Decreased pTyr of a protein shows that the said protein is a substrate of the PTPase or PTPases that are inhibited by the compounds of the invention. Having identified and visualized proteins, i.e. substrates, that show decreased pTyr levels, the spots are cut out, digested with trypsin and analyzed by matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) (Marcus et al., supra). To identify the nature of said substrate with decreased pTyr levels the obtained mass fingerprints are analyzed as described by Marcus et al. (supra) or other methods well-known to those skilled in the art.
Said substrate can either be an already described protein or a novel protein. In both cases, the identification may be followed by cDNA cloning procedures with the aim of obtaining a full-length clone corresponding to said substrate using standard techniques well-know to those skilled in the art (Ausubel, F. M., et al. (ED.). Short protocols in molecular biology, 2nd ed, John Wiley and sons, inc., New York, ISBN 0-471-57735-9 (1992)). Further use of the knowledge include analysis in animal models as described in Example 59
Example 123
Analysis for Blood Glucose Lowering Effects
The compounds of the invention are tested for blood glucose lowering effects in diabetic, obese female ob/ob mice. The mice are of similar age and body weights and they are randomized into groups of ten mice. They have free access to food and water during the experiment. The compounds are administered by either by gavage, subcutaneous, intravenous or intraperitoneal injections. The control group receives the same volume of vehicle as the mice that receive the compounds. Non-limiting examples of dose-range: 0.1, 0.3, 1.0, 3.0, 10, 30, 100 mg per kg body weight. The blood glucose levels are measured two times before administration of the compounds of the invention and vehicle (to the control group). After administration of the compound, the blood glucose levels are measured at the following time points: 1, 2, 4, 6, and 8 hours. A positive response is defined either as (i) a more than 25 percent reduction in blood glucose levels in the group receiving the compound of the invention compared to the group receiving the vehicle at any time point or (ii) statistically significant (i.e. p<0.05) reduction in the area under the blood glucose curve during the whole period (i.e. 8 hrs) in the group treated with the compounds of the invention compared to the group receiving the vehicle.
All documents cited herein are incorporated by reference in their entirety. In case of conflict in definitions, the present definitions control.







TABLE A







Table of the orthogonal three dimensional coordinates in Ångstroms and B


factors (Å2) for Protein Tyrosine Phosphatase 1B complexed with 2-(oxalyl-


amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid.












No
Amino acid
X
Y
Z
B
















1
GLU
N
69.819
14.736
20.949
51.88


2
GLU
CA
69.381
16.070
20.592
50.12


3
GLU
C
68.816
16.123
19.177
50.96


4
GLU
O
69.477
15.855
18.147
47.57


5
GLU
CB
70.340
17.247
20.871
48.87


6
GLU
CG
69.694
18.607
20.512
43.78


7
GLU
CD
68.658
19.051
21.547
100.00


8
GLU
OE1
68.838
19.978
22.327
100.00


9
GLU
OE2
67.553
18.331
21.549
100.00


10
MET
N
67.550
16.476
19.190
38.96


11
MET
CA
66.810
16.619
18.000
33.41


12
MET
C
67.438
17.710
17.211
32.40


13
MET
O
67.335
17.745
16.010
34.44


14
MET
CB
65.376
17.042
18.345
34.94


15
MET
CG
65.321
18.129
19.414
36.89


16
MET
SD
63.595
18.598
19.738
37.03


17
MET
CE
63.053
17.127
20.689
35.19


18
GLU
N
68.060
18.625
17.893
31.60


19
GLU
CA
68.666
19.756
17.226
34.56


20
GLU
C
69.903
19.379
16.393
37.49


21
GLU
O
70.082
19.836
15.267
37.90


22
GLU
CB
68.955
20.859
18.236
36.57


23
GLU
CG
68.694
22.256
17.685
54.02


24
GLU
CD
68.602
23.271
18.792
84.59


25
GLU
OE1
68.338
22.965
19.970
60.30


26
GLU
OE2
68.826
24.499
18.340
56.97


27
LYS
N
70.740
18.506
16.928
34.63


28
LYS
CA
71.925
18.073
16.173
36.36


29
LYS
C
71.504
17.225
14.995
35.30


30
LYS
O
72.071
17.271
13.926
33.46


31
LYS
CB
72.858
17.280
17.069
44.20


32
LYS
CG
73.694
18.196
17.980
95.46


33
LYS
CD
74.837
17.496
18.729
100.00


34
LYS
CE
74.640
17.419
20.241
98.28


35
LYS
NZ
73.758
16.304
20.653
100.00


36
GLU
N
70.463
16.441
15.234
32.09


37
GLU
CA
69.894
15.573
14.227
31.58


38
GLU
C
69.285
16.367
13.096
33.03


39
GLU
O
69.380
16.076
11.917
33.46


40
GLU
CB
68.841
14.653
14.863
33.60


41
GLU
CG
67.823
14.152
13.814
51.32


42
GLU
CD
66.936
13.044
14.309
61.90


43
GLU
OE1
66.302
13.085
15.370
49.63


44
GLU
OE2
66.918
12.042
13.457
46.46


45
PHE
N
68.648
17.422
13.475
31.95


46
PHE
CA
68.008
18.269
12.488
32.19


47
PHE
C
69.072
18.712
11.539
37.60


48
PHE
O
68.928
18.630
10.309
32.52


49
PHE
CB
67.340
19.508
13.152
32.26


50
PHE
CG
66.508
20.348
12.196
30.98


51
PHE
CD1
65.161
20.064
11.967
29.63


52
PHE
CD2
67.094
21.402
11.499
29.81


53
PHE
CE1
64.398
20.834
11.096
31.86


54
PHE
CE2
66.354
22.185
10.621
32.68


55
PHE
CZ
65.004
21.896
10.423
34.10


56
GLU
N
70.164
19.160
12.179
36.63


57
GLU
CA
71.310
19.627
11.440
36.44


58
GLU
C
71.889
18.598
10.519
37.22


59
GLU
O
72.034
18.827
9.312
41.43


60
GLU
CB
72.309
20.346
12.308
40.39


61
GLU
CG
71.810
21.794
12.529
71.18


62
GLU
CD
71.946
22.266
13.953
100.00


63
GLU
OE1
72.735
21.752
14.751
100.00


64
GLU
OE2
71.139
23.288
14.223
100.00


65
GLN
N
72.140
17.413
11.024
31.25


66
GLN
CA
72.622
16.443
10.091
30.97


67
GLN
C
71.717
16.227
8.911
37.58


68
GLN
O
72.187
16.205
7.798
35.23


69
GLN
CB
72.828
15.118
10.746
32.09


70
GLN
CG
73.907
15.196
11.804
59.96


71
GLN
CD
74.286
13.786
12.123
100.00


72
GLN
OE1
73.653
12.854
11.579
100.00


73
GLN
NE2
75.309
13.631
12.975
100.00


74
ILE
N
70.403
16.026
9.164
37.32


75
ILE
CA
69.439
15.745
8.091
33.95


76
ILE
C
69.451
16.857
7.112
35.04


77
ILE
O
69.497
16.713
5.871
32.60


78
ILE
CB
68.007
15.516
8.591
33.88


79
ILE
CG1
67.983
14.281
9.450
33.37


80
ILE
CG2
67.062
15.263
7.427
27.69


81
ILE
CD1
66.734
14.241
10.340
41.16


82
ASP
N
69.392
17.990
7.705
31.68


83
ASP
CA
69.374
19.138
6.893
34.74


84
ASP
C
70.643
19.193
6.028
45.86


85
ASP
O
70.614
19.383
4.778
46.01


86
ASP
CB
69.131
20.360
7.773
36.60


87
ASP
CG
67.950
21.114
7.297
41.28


88
ASP
OD1
67.080
20.557
6.700
43.16


89
ASP
OD2
67.978
22.408
7.544
44.81


90
LYS
N
71.777
19.003
6.699
41.67


91
LYS
CA
73.008
19.033
5.954
43.82


92
LYS
C
73.035
17.928
4.864
46.27


93
LYS
O
73.357
18.177
3.709
45.13


94
LYS
CB
74.246
19.032
6.859
48.59


95
LYS
CG
74.736
17.622
7.242
93.12


96
LYS
CD
75.455
17.518
8.604
100.00


97
LYS
CE
76.327
16.267
8.797
100.00


98
LYS
NZ
75.740
15.262
9.683
100.00


99
SER
N
72.692
16.706
5.240
40.90


100
SER
CA
72.713
15.593
4.309
41.87


101
SER
C
71.575
15.604
3.324
48.03


102
SER
O
71.464
14.678
2.502
46.24


103
SER
CB
72.726
14.225
4.998
47.13


104
SER
OG
72.148
14.254
6.292
62.32


105
GLY
N
70.729
16.629
3.441
45.84


106
GLY
CA
69.560
16.743
2.595
46.85


107
GLY
C
68.809
15.410
2.577
51.28


108
GLY
O
68.437
14.883
1.532
56.29


109
SER
N
68.578
14.814
3.724
41.13


110
SER
CA
67.894
13.545
3.650
37.67


111
SER
C
66.529
13.420
4.344
33.83


112
SER
O
66.192
12.328
4.793
32.66


113
SER
CB
68.822
12.442
4.043
39.40


114
SER
OG
69.368
12.791
5.268
49.16


115
TRP
N
65.719
14.495
4.371
28.03


116
TRP
CA
64.390
14.413
4.947
24.69


117
TRP
C
63.521
13.375
4.242
30.79


118
TRP
O
62.773
12.639
4.915
30.44


119
TRP
CB
63.700
15.754
4.922
24.38


120
TRP
CG
64.317
16.654
5.925
24.63


121
TRP
CD1
65.208
17.670
5.685
27.42


122
TRP
CD2
64.101
16.581
7.359
22.65


123
TRP
NE1
65.553
18.274
6.893
27.47


124
TRP
CE2
64.916
17.588
7.946
28.99


125
TRP
CE3
63.346
15.749
8.195
21.13


126
TRP
CZ2
64.926
17.778
9.345
24.85


127
TRP
CZ3
63.385
15.932
9.554
20.43


128
TRP
CH2
64.168
16.938
10.115
21.06


129
ALA
N
63.620
13.268
2.876
26.09


130
ALA
CA
62.799
12.286
2.153
24.22


131
ALA
C
63.096
10.865
2.571
28.29


132
ALA
O
62.214
10.029
2.737
27.06


133
ALA
CB
62.920
12.477
0.652
25.69


134
ALA
N
64.363
10.580
2.794
26.20


135
ALA
CA
64.704
9.238
3.195
26.43


136
ALA
C
64.197
8.932
4.602
31.50


137
ALA
O
63.581
7.885
4.927
27.14


138
ALA
CB
66.210
9.022
3.107
26.43


139
ILE
N
64.482
9.876
5.467
28.04


140
ILE
CA
64.042
9.728
6.826
25.50


141
ILE
C
62.562
9.449
6.863
27.81


142
ILE
O
62.053
8.525
7.520
28.96


143
ILE
CB
64.267
11.063
7.477
28.83


144
ILE
CG1
65.751
11.246
7.430
30.75


145
ILE
CG2
63.815
11.019
8.941
29.55


146
ILE
CD1
66.368
10.532
8.621
40.82


147
TYR
N
61.873
10.317
6.156
25.16


148
TYR
CA
60.436
10.229
6.111
24.00


149
TYR
C
59.987
8.882
5.562
28.75


150
TYR
O
59.127
8.228
6.160
24.95


151
TYR
CB
59.814
11.445
5.419
23.47


152
TYR
CG
58.290
11.319
5.304
24.07


153
TYR
CD1
57.449
11.372
6.424
25.26


154
TYR
CD2
57.674
11.154
4.064
24.94


155
TYR
CE1
56.060
11.231
6.357
22.60


156
TYR
CE2
56.279
11.044
3.962
24.32


157
TYR
CZ
55.470
11.103
5.101
22.19


158
TYR
OH
54.112
11.014
4.979
21.43


159
GLN
N
60.604
8.446
4.440
26.68


160
GLN
CA
60.271
7.134
3.869
25.28


161
GLN
C
60.553
6.006
4.861
26.17


162
GLN
O
59.857
4.992
4.963
26.54


163
GLN
CB
61.021
6.871
2.543
27.78


164
GLN
CG
62.409
6.217
2.796
84.03


165
GLN
CD
63.607
6.501
1.839
100.00


166
GLN
OE1
64.737
6.062
2.164
98.42


167
GLN
NE2
63.414
7.188
0.676
76.48


168
ASP
N
61.596
6.176
5.640
24.54


169
ASP
CA
61.862
5.128
6.590
28.47


170
ASP
C
60.721
4.997
7.550
29.84


171
ASP
O
60.290
3.884
7.886
28.51


172
ASP
CB
63.220
5.284
7.314
35.64


173
ASP
CG
64.331
5.565
6.310
80.96


174
ASP
OD1
64.144
5.579
5.099
89.73


175
ASP
OD2
65.510
5.815
6.842
91.88


176
ILE
N
60.210
6.141
7.974
24.27


177
ILE
CA
59.060
6.052
8.889
24.52


178
ILE
C
57.903
5.367
8.255
24.70


179
ILE
O
57.252
4.522
8.841
25.35


180
ILE
CB
58.619
7.415
9.401
27.95


181
ILE
CG1
59.610
7.838
10.487
28.44


182
ILE
CG2
57.225
7.315
9.999
23.89


183
ILE
CD1
59.930
9.302
10.343
27.02


184
ARG
N
57.646
5.725
7.020
22.44


185
ARG
CA
56.511
5.098
6.330
22.70


186
ARG
C
56.702
3.601
6.226
26.26


187
ARG
O
55.761
2.788
6.333
23.08


188
ARG
CB
56.366
5.662
4.905
27.59


189
ARG
CG
55.825
7.104
4.773
27.34


190
ARG
CD
55.228
7.330
3.376
30.48


191
ARG
NE
54.182
8.369
3.362
86.57


192
ARG
CZ
53.614
8.942
2.268
100.00


193
ARG
NH1
53.954
8.615
1.006
100.00


194
ARG
NH2
52.685
9.890
2.445
33.19


195
HIS
N
57.967
3.235
5.974
26.18


196
HIS
CA
58.297
1.840
5.840
28.26


197
HIS
C
57.980
0.991
7.099
30.43


198
HIS
O
57.474
−0.179
7.075
22.68


199
HIS
CB
59.770
1.728
5.431
32.89


200
HIS
CG
60.149
0.296
5.206
42.37


201
HIS
ND1
60.626
−0.504
6.250
47.99


202
HIS
CD2
60.082
−0.474
4.078
47.47


203
HIS
CE1
60.816
−1.726
5.745
48.95


204
HIS
NE2
60.502
−1.747
4.449
48.75


205
GLU
N
58.321
1.588
8.255
30.06


206
GLU
CA
58.143
0.866
9.524
28.09


207
GLU
C
56.806
1.041
10.196
27.30


208
GLU
O
56.503
0.399
11.193
27.94


209
GLU
CB
59.244
1.273
10.531
30.97


210
GLU
CG
60.629
1.547
9.904
54.48


211
GLU
CD
61.444
2.586
10.685
100.00


212
GLU
OE1
61.742
2.444
11.872
100.00


213
GLU
OE2
61.812
3.644
9.973
100.00


214
ALA
N
55.999
1.936
9.673
21.78


215
ALA
CA
54.703
2.217
10.276
19.05


216
ALA
C
53.882
0.959
10.372
26.56


217
ALA
O
53.939
0.125
9.462
25.40


218
ALA
CB
53.944
3.236
9.423
20.42


219
SER
N
53.081
0.847
11.465
21.44


220
SER
CA
52.234
−0.307
11.732
19.39


221
SER
C
51.225
−0.517
10.663
27.89


222
SER
O
50.657
0.440
10.137
25.51


223
SER
CB
51.412
−0.049
12.974
21.80


224
SER
OG
52.257
0.317
14.021
26.89


225
ASP
N
50.935
−1.779
10.428
27.10


226
ASP
CA
49.936
−2.129
9.448
29.07


227
ASP
C
48.895
−2.997
10.125
30.02


228
ASP
O
49.166
−4.133
10.484
31.00


229
ASP
CB
50.631
−2.786
8.250
33.50


230
ASP
CG
49.690
−3.348
7.216
50.19


231
ASP
OD1
48.519
−3.040
7.156
46.03


232
ASP
OD2
50.278
−4.185
6.378
67.71


233
PHE
N
47.737
−2.422
10.384
20.70


234
PHE
CA
46.675
−3.127
11.085
19.53


235
PHE
C
45.446
−3.117
10.216
25.93


236
PHE
O
45.307
−2.281
9.357
28.17


237
PHE
CB
46.339
−2.422
12.436
19.46


238
PHE
CG
47.428
−2.504
13.514
18.83


239
PHE
CD1
47.752
−3.720
14.138
19.35


240
PHE
CD2
48.062
−1.346
13.989
17.72


241
PHE
CE1
48.753
−3.782
15.118
19.95


242
PHE
CE2
49.088
−1.384
14.939
21.08


243
PHE
CZ
49.410
−2.611
15.530
20.14


244
PRO
N
44.534
−4.031
10.446
23.52


245
PRO
CA
43.331
−4.115
9.640
21.50


246
PRO
C
42.303
−3.001
9.968
23.90


247
PRO
O
42.217
−2.497
11.117
22.13


248
PRO
CB
42.675
−5.448
10.030
22.86


249
PRO
CG
43.276
−5.845
11.381
29.00


250
PRO
CD
44.623
−5.147
11.450
24.62


251
CYS
N
41.517
−2.717
8.941
19.44


252
CYS
CA
40.442
−1.753
8.931
21.26


253
CYS
C
39.268
−2.405
8.253
24.35


254
CYS
O
38.706
−1.890
7.289
23.90


255
CYS
CB
40.832
−0.547
8.032
24.83


256
CYS
SG
42.442
0.202
8.391
31.37


257
ARG
N
38.910
−3.578
8.709
21.13


258
ARG
CA
37.877
−4.281
8.029
19.87


259
ARC
C
36.558
−3.582
8.150
24.13


260
ARG
O
35.758
−3.569
7.221
22.22


261
ARG
CB
37.842
−5.706
8.532
29.48


262
ARG
CG
36.735
−5.804
9.576
76.36


263
ARG
GD
36.827
−7.051
10.450
94.77


264
ARG
NE
36.033
−6.953
11.671
78.60


265
ARG
CZ
34.718
−6.843
11.637
91.25


266
ARG
NH1
34.073
−6.801
10.466
65.21


267
ARG
NH2
34.032
−6.768
12.785
88.97


268
VAL
N
36.307
−2.961
9.284
19.02


269
VAL
CA
35.034
−2.288
9.372
17.46


270
VAL
C
34.925
−1.135
8.397
21.91


271
VAL
O
33.923
−0.950
7.725
25.41


272
VAL
CB
34.726
−1.775
10.740
17.65


273
VAL
CG1
33.338
−1.205
10.712
17.50


274
VAL
CG2
34.778
−2.908
11.719
19.97


275
ALA
N
35.964
−0.367
8.277
17.06


276
ALA
CA
35.933
0.744
7.364
17.17


277
ALA
C
35.664
0.295
5.949
26.79


278
ALA
O
35.129
1.038
5.135
23.44


279
ALA
CB
37.320
1.378
7.356
16.97


280
LYS
N
36.118
−0.899
5.645
21.85


281
LYS
CA
35.993
−1.403
4.299
23.03


282
LYS
C
34.718
−2.121
4.012
26.65


283
LYS
O
34.497
−2.565
2.898
29.21


284
LYS
CB
37.201
−2.228
3.868
28.38


285
LYS
CG
38.442
−1.359
3.651
30.93


286
LYS
CD
38.066
−0.075
2.926
50.71


287
LYS
CE
39.121
0.512
1.999
52.15


288
LYS
NZ
38.518
1.459
1.033
53.44


289
LEU
N
33.855
−2.250
4.983
26.04


290
LEU
CA
32.594
−2.885
4.664
24.42


291
LEU
C
31.830
−2.075
3.603
30.28


292
LEU
O
31.830
−0.856
3.588
26.94


293
LEU
CB
31.754
−2.820
5.907
25.29


294
LEU
CG
31.721
−4.091
6.733
31.05


295
LEU
CD1
32.743
−5.118
6.282
30.64


296
LEU
CD2
31.726
−3.789
8.213
25.61


297
PRO
N
31.131
−2.743
2.705
33.21


298
PRO
CA
30.345
−2.081
1.660
32.26


299
PRO
C
29.470
−0.982
2.155
29.80


300
PRO
O
29.435
0.086
1.598
28.50


301
PRO
CB
29.358
−3.139
1.155
35.94


302
PRO
CG
29.790
−4.443
1.815
42.24


303
PRO
CD
31.159
−4.194
2.448
36.58


304
LYS
N
28.732
−1.278
3.191
29.93


305
LYS
CA
27.805
−0.291
3.727
29.87


306
LYS
C
28.449
1.003
4.192
32.15


307
LYS
O
27.751
2.019
4.352
29.62


308
LYS
CB
26.915
−0.840
4.835
28.99


309
LYS
CG
27.683
−1.496
5.963
32.04


310
LYS
CD
26.911
−1.359
7.260
40.42


311
LYS
CE
27.142
−2.452
8.303
54.33


312
LYS
NZ
26.267
−2.273
9.466
72.90


313
ASN
N
29.760
0.960
4.440
25.44


314
ASN
CA
30.439
2.153
4.930
24.36


315
ASN
C
31.136
2.942
3.817
25.64


316
ASN
O
31.853
3.900
4.038
22.73


317
ASN
CB
31.454
1.740
6.025
21.85


318
ASN
CG
30.756
1.221
7.234
27.10


319
ASN
OD1
29.741
1.774
7.597
21.43


320
ASN
ND2
31.308
0.206
7.912
22.00


321
LYS
N
30.958
2.531
2.601
23.30


322
LYS
CA
31.685
3.175
1.546
23.68


323
LYS
C
31.498
4.684
1.542
26.11


324
LYS
O
32.434
5.476
1.385
22.38


325
LYS
CB
31.187
2.608
0.225
26.88


326
LYS
CG
32.036
2.987
−0.968
54.66


327
LYS
CD
32.007
1.947
−2.079
92.45


328
LYS
CE
31.689
2.503
−3.474
100.00


329
LYS
NZ
31.185
1.538
−4.438
100.00


330
ASN
N
30.233
5.068
1.662
22.80


331
ASN
CA
29.878
6.469
1.650
21.26


332
ASN
C
30.177
7.203
2.973
24.59


333
ASN
O
29.802
8.367
3.135
21.48


334
ASN
CB
28.430
6.739
1.159
19.81


335
ASN
CG
27.389
6.329
2.191
32.17


336
ASN
OD1
27.700
5.966
3.344
25.99


337
ASN
ND2
26.147
6.335
1.765
32.33


338
ARG
N
30.877
6.548
3.904
20.39


339
ARG
CA
31.241
7.201
5.150
18.64


340
ARG
C
32.702
7.535
5.136
20.09


341
ARG
O
33.225
8.042
6.113
20.82


342
ARG
CB
30.866
6.366
6.369
15.80


343
ARG
CG
29.337
6.275
6.511
24.13


344
ARG
CD
28.894
5.471
7.752
21.03


345
ARG
NE
27.448
5.428
7.873
21.48


346
ARG
CZ
26.841
5.336
9.030
28.21


347
ARG
NH1
27.509
5.294
10.182
18.63


348
ARG
NH2
25.519
5.288
9.033
23.12


349
ASN
N
33.389
7.218
4.039
18.29


350
ASN
CA
34.816
7.469
3.950
17.44


351
ASN
C
35.125
8.452
2.881
20.28


352
ASN
O
34.710
8.264
1.761
19.07


353
ASN
CB
35.593
6.181
3.663
15.55


354
ASN
CG
35.466
5.220
4.807
17.95


355
ASN
OD1
35.682
5.568
5.952
17.27


356
ASN
ND2
35.117
3.964
4.489
18.68


357
ARG
N
35.848
9.504
3.241
17.03


358
ARG
CA
36.149
10.550
2.276
16.04


359
ARG
C
37.140
10.084
1.227
21.28


360
ARG
O
37.000
10.388
0.049
17.65


361
ARG
CB
36.633
11.840
2.983
13.55


362
ARG
CG
37.024
12.938
2.016
13.76


363
ARG
CD
37.420
14.200
2.774
16.51


364
ARG
NE
36.224
14.791
3.392
18.16


365
ARG
CZ
35.306
15.542
2.703
26.85


366
ARG
NH1
35.365
15.811
1.381
20.84


367
ARG
NH2
34.234
16.012
3.341
16.64


368
TYR
N
38.164
9.354
1.679
17.86


369
TYR
CA
39.233
8.872
0.832
15.41


370
TYR
C
39.411
7.359
0.980
22.83


371
TYR
O
39.443
6.781
2.075
16.42


372
TYR
CB
40.562
9.498
1.157
14.29


373
TYR
CG
40.539
11.006
1.106
18.83


374
TYR
CD1
40.543
11.605
−0.152
18.23


375
TYR
CD2
40.543
11.799
2.270
17.14


376
TYR
CE1
40.467
12.989
−0.282
17.99


377
TYR
CE2
40.519
13.195
2.150
16.12


378
TYR
CZ
40.508
13.767
0.872
18.16


379
TYR
OH
40.491
15.147
0.711
18.89


380
ARG
N
39.483
6.735
−0.189
21.95


381
ARG
CA
39.577
5.315
−0.261
21.42


382
ARG
C
40.844
4.775
0.390
18.55


383
ARG
O
40.869
3.647
0.838
20.34


384
ARG
CB
39.306
4.858
−1.720
21.50


385
ARG
CG
40.427
4.051
−2.346
62.10


386
ARG
CD
41.233
4.684
−3.494
83.64


387
ARG
NE
42.611
4.161
−3.438
100.00


388
ARG
CZ
43.771
4.841
−3.523
100.00


389
ARG
NH1
43.842
6.149
−3.796
52.01


390
ARG
NH2
44.910
4.155
−3.451
95.71


391
ASP
N
41.862
5.576
0.492
14.95


392
ASP
CA
43.082
5.093
1.065
15.39


393
ASP
C
43.336
5.554
2.490
20.93


394
ASP
O
44.434
5.386
3.007
20.89


395
ASP
CB
44.260
5.583
0.229
16.63


396
ASP
CG
44.232
7.082
0.082
22.24


397
ASP
OD1
43.217
7.738
0.070
21.30


398
ASP
OD2
45.394
7.561
−0.238
19.13


399
VAL
N
42.347
6.156
3.118
16.50


400
VAL
CA
42.521
6.606
4.512
15.25


401
VAL
C
41.410
6.066
5.346
14.75


402
VAL
O
40.238
6.504
5.271
14.44


403
VAL
CB
42.451
8.123
4.686
17.27


404
VAL
CG1
42.721
8.517
6.182
13.83


405
VAL
CG2
43.493
8.755
3.753
16.91


406
SER
N
41.767
5.113
6.158
15.99


407
SER
CA
40.760
4.485
6.993
17.42


408
SER
C
41.244
4.320
8.405
19.32


409
SER
O
42.424
4.173
8.656
18.77


410
SER
CB
40.514
3.028
6.484
22.19


411
SER
OG
40.054
3.029
5.131
21.85


412
PRO
N
40.292
4.229
9.316
17.04


413
PRO
CA
40.684
3.951
10.686
14.95


414
PRO
C
40.991
2.428
10.873
21.72


415
PRO
O
40.275
1.571
10.353
21.93


416
PRO
CB
39.423
4.252
11.548
14.87


417
PRO
CG
38.238
4.153
10.604
18.96


418
PRO
CD
38.800
4.338
9.177
15.06


419
PHE
N
42.019
2.096
11.691
19.00


420
PHE
CA
42.266
0.711
12.046
16.26


421
PHE
C
41.099
0.239
12.907
20.51


422
PHE
O
40.517
0.996
13.712
18.21


423
PHE
CB
43.484
0.629
12.972
16.62


424
PHE
CG
44.768
0.998
12.290
16.69


425
PHE
CD1
45.003
0.566
10.991
17.42


426
PHE
CD2
45.748
1.751
12.951
16.19


427
PHE
CE1
46.217
0.883
10.383
17.05


428
PHE
CE2
46.957
2.090
12.351
17.24


429
PHE
CZ
47.157
1.686
11.030
15.76


430
ASP
N
40.774
−1.056
12.819
19.69


431
ASP
CA
39.725
−1.541
13.645
19.38


432
ASP
C
40.050
−1.394
15.135
22.03


433
ASP
O
39.169
−1.155
15.966
20.90


434
ASP
CB
39.442
−3.033
13.331
21.07


435
ASP
CG
38.887
−3.204
11.964
26.66


436
ASP
OD1
38.132
−2.404
11.443
25.86


437
ASP
OD2
39.391
−4.217
11.336
29.95


438
HIS
N
41.288
−1.623
15.513
16.04


439
HIS
CA
41.509
−1.608
16.924
16.58


440
HIS
C
41.355
−0.281
17.634
25.32


441
HIS
O
41.100
−0.239
18.870
24.53


442
HIS
CB
42.856
−2.240
17.272
15.76


443
HIS
CG
44.037
−1.338
17.088
17.63


444
HIS
ND1
44.449
−0.441
18.079
19.17


445
HIS
CD2
44.890
−1.230
16.041
16.56


446
HIS
CE1
45.560
0.159
17.644
17.00


447
HIS
NE2
45.831
−0.298
16.427
17.69


448
SER
N
41.535
0.808
16.896
18.44


449
SER
CA
41.467
2.102
17.571
17.07


450
SER
C
40.307
2.966
17.101
24.02


451
SER
O
40.171
4.125
17.523
19.51


452
SER
CB
42.776
2.867
17.350
17.91


453
SER
OG
43.130
2.848
15.967
17.63


454
ARG
N
39.469
2.429
16.223
18.61


455
ARG
CA
38.403
3.278
15.711
17.44


456
ARG
C
37.438
3.714
16.763
21.37


457
ARG
O
37.179
2.969
17.729
21.12


458
ARG
CB
37.602
2.640
14.577
20.23


459
ARG
CG
36.621
1.515
15.009
21.54


460
ARG
CD
35.968
0.725
13.835
24.77


461
ARG
NE
34.948
−0.234
14.300
23.61


462
ARG
CZ
33.667
0.024
14.419
28.43


463
ARG
NH1
33.166
1.215
14.106
17.26


464
ARG
NH2
32.865
−0.945
14.886
22.24


465
ILE
N
36.814
4.891
16.529
20.42


466
ILE
CA
35.777
5.390
17.455
17.73


467
ILE
C
34.431
4.780
17.042
23.53


468
ILE
O
34.021
4.855
15.864
19.57


469
ILE
CB
35.640
6.925
17.449
18.61


470
ILE
CG1
36.949
7.648
17.816
16.90


471
ILE
CG2
34.493
7.340
18.369
19.54


472
ILE
CD1
37.390
7.446
19.280
23.50


473
LYS
N
33.724
4.181
18.014
17.77


474
LYS
CA
32.479
3.661
17.638
19.44


475
LYS
C
31.329
4.585
18.080
23.14


476
LYS
O
31.307
5.073
19.222
23.03


477
LYS
CB
32.343
2.312
18.288
25.11


478
LYS
CG
33.271
1.269
17.706
28.50


479
LYS
CD
32.904
−0.078
18.301
42.01


480
LYS
CE
34.060
−1.057
18.404
50.09


481
LYS
NZ
33.628
−2.377
18.900
65.13


482
LEU
N
30.358
4.822
17.187
19.37


483
LEU
CA
29.173
5.650
17.536
19.21


484
LEU
C
28.311
4.790
18.451
30.47


485
LEU
O
28.311
3.555
18.264
27.66


486
LEU
CB
28.346
5.917
16.283
18.17


487
LEU
CG
29.225
6.632
15.268
20.04


488
LEU
CD1
28.533
6.828
13.952
17.50


489
LEU
CD2
29.630
7.998
15.864
17.41


490
HIS
N
27.616
5.406
19.435
24.92


491
HIS
CA
26.790
4.616
20.333
23.96


492
HIS
C
25.439
4.506
19.717
34.63


493
HIS
O
24.491
5.195
20.064
38.67


494
HIS
CB
26.695
5.217
21.719
24.41


495
HIS
CG
28.030
5.381
22.372
29.98


496
HIS
ND1
28.197
6.121
23.570
33.91


497
HIS
CD2
29.258
4.908
21.994
31.10


498
HIS
CE1
29.504
6.052
23.881
33.12


499
HIS
NE2
30.159
5.332
22.951
32.31


500
GLN
N
25.367
3.685
18.712
38.08


501
GLN
CA
24.103
3.522
18.003
41.99


502
GLN
C
24.077
2.125
17.437
46.43


503
GLN
O
25.111
1.523
17.202
42.03


504
GLN
CB
23.751
4.631
16.958
43.94


505
GLN
CG
24.597
4.425
15.691
50.12


506
GLN
CD
24.204
5.284
14.508
78.89


507
GLN
OE1
24.235
6.526
14.622
72.88


508
GLN
NE2
23.934
4.636
13.354
62.05


509
GLU
N
22.876
1.603
17.293
50.52


510
GLU
CA
22.676
0.234
16.832
53.51


511
GLU
C
22.637
0.058
15.328
53.08


512
GLU
O
23.006
−0.999
14.825
48.73


513
GLU
CB
21.441
−0.418
17.510
56.24


514
GLU
CG
21.550
−0.429
19.051
74.99


515
GLU
CD
20.383
−1.136
19.705
100.00


516
GLU
OE1
19.203
−0.939
19.368
100.00


517
GLU
OE2
20.768
−2.009
20.636
100.00


518
ASP
N
22.170
1.083
14.619
50.94


519
ASP
CA
22.101
0.990
13.183
52.56


520
ASP
C
23.492
0.706
12.532
50.81


521
ASP
O
23.723
−0.285
11.795
54.32


522
ASP
CB
21.388
2.250
12.634
57.77


523
ASP
CG
21.808
2.668
11.243
94.02


524
ASP
OD1
21.577
1.977
10.250
99.87


525
ASP
OD2
22.439
3.847
11.214
100.00


526
ASN
N
24.444
1.597
12.808
34.60


527
ASN
CA
25.773
1.475
12.236
28.07


528
ASN
C
26.669
2.345
13.088
29.15


529
ASN
O
26.536
3.556
13.101
30.48


530
ASN
CB
25.734
2.022
10.803
19.62


531
ASN
CG
27.024
1.823
10.062
27.76


532
ASN
OD1
28.067
1.547
10.679
22.79


533
ASN
ND2
26.967
1.995
8.729
21.65


534
ASP
N
27.600
1.752
13.806
22.25


535
ASP
CA
28.430
2.534
14.667
20.02


536
ASP
C
29.676
3.124
14.011
22.15


537
ASP
O
30.575
3.603
14.710
22.95


538
ASP
CB
28.858
1.548
15.757
21.84


539
ASP
CG
29.803
0.461
15.282
26.22


540
ASP
OD1
30.328
0.421
14.195
26.63


541
ASP
OD2
30.146
−0.355
16.235
35.64


542
TYR
N
29.794
3.001
12.697
19.04


543
TYR
CA
31.033
3.440
12.034
16.92


544
TYR
C
31.184
4.931
11.701
22.03


545
TYR
O
30.325
5.601
11.107
22.84


546
TYR
CB
31.149
2.733
10.691
16.06


547
TYR
CG
32.412
3.169
9.987
17.61


548
TYR
CD1
33.645
2.670
10.425
20.91


549
TYR
CD2
32.403
4.043
8.886
16.20


550
TYR
CE1
34.857
3.065
9.828
19.50


551
TYR
CE2
33.596
4.460
8.282
13.17


552
TYR
CZ
34.818
3.973
8.769
14.97


553
TYR
OH
36.004
4.360
8.214
18.92


554
ILE
N
32.319
5.440
12.061
19.32


555
ILE
CA
32.752
6.780
11.682
17.75


556
ILE
C
34.257
6.676
11.366
16.65


557
ILE
O
35.022
5.912
11.984
14.78


558
ILE
CB
32.460
7.883
12.709
18.72


559
ILE
CG1
32.923
9.269
12.196
17.13


560
ILE
CG2
33.132
7.524
14.066
19.79


561
ILE
CD1
32.357
10.364
13.106
16.24


562
ASN
N
34.721
7.445
10.394
14.05


563
ASN
CA
36.134
7.408
10.072
12.04


564
ASN
C
36.861
8.263
11.062
18.49


565
ASN
O
37.028
9.462
10.808
16.53


566
ASN
CB
36.392
7.908
8.637
10.31


567
ASN
CG
37.806
7.615
8.161
18.51


568
ASN
OD1
38.803
7.928
8.840
17.25


569
ASN
ND2
37.914
7.096
6.948
13.86


570
ALA
N
37.206
7.670
12.215
15.81


571
ALA
CA
37.822
8.363
13.318
15.05


572
ALA
C
38.551
7.400
14.203
17.50


573
ALA
O
38.093
6.297
14.414
15.99


574
ALA
CB
36.768
9.111
14.121
15.21


575
SER
N
39.670
7.856
14.752
13.78


576
SER
CA
40.518
7.002
15.565
14.32


577
SER
C
40.915
7.650
16.857
16.94


578
SER
O
41.210
8.834
16.908
18.12


579
SER
CB
41.859
6.766
14.820
15.23


580
SER
OG
41.642
6.232
13.488
17.37


581
LEU
N
41.046
6.853
17.898
15.51


582
LEU
CA
41.503
7.396
19.161
15.13


583
LEU
C
43.015
7.175
19.229
22.22


584
LEU
O
43.454
6.029
19.128
21.68


585
LEU
CB
40.801
6.641
20.374
16.59


586
LEU
CG
41.333
6.988
21.784
19.94


587
LEU
CD1
41.053
8.438
22.118
20.86


588
LEU
CD2
40.611
6.204
22.847
21.37


589
ILE
N
43.797
8.247
19.421
17.07


590
ILE
CA
45.219
8.168
19.506
16.19


591
ILE
C
45.524
8.335
20.995
24.53


592
ILE
O
45.338
9.380
21.568
22.94


593
ILE
CB
45.845
9.330
18.796
18.65


594
ILE
CG1
45.927
9.229
17.286
18.37


595
ILE
CG2
47.265
9.378
19.290
21.51


596
ILE
CD1
44.791
8.564
16.611
25.42


597
LYS
N
45.955
7.285
21.664
20.46


598
LYS
CA
46.162
7.350
23.092
20.79


599
LYS
C
47.630
7.299
23.390
24.25


600
LYS
O
48.236
6.260
23.159
24.06


601
LYS
CB
45.396
6.160
23.699
24.07


602
LYS
CG
44.960
6.286
25.154
48.81


603
LYS
CD
44.128
5.081
25.617
70.96


604
LYS
CE
44.276
4.756
27.109
99.34


605
LYS
NZ
44.076
3.328
27.445
100.00


606
MET
N
48.201
8.455
23.822
22.51


607
MET
CA
49.625
8.581
24.124
20.07


608
MET
C
49.859
8.290
25.599
27.14


609
MET
O
49.758
9.141
26.462
24.51


610
MET
CB
50.266
9.882
23.647
19.62


611
MET
CG
50.032
10.097
22.162
21.13


612
MET
SD
50.570
8.761
21.081
23.27


613
MET
CE
52.316
9.093
21.055
18.81


614
GLU
N
50.136
7.023
25.830
28.15


615
GLU
CA
50.280
6.525
27.160
29.78


616
GLU
C
51.248
7.321
28.030
34.27


617
GLU
O
50.881
7.991
29.015
33.62


618
GLU
CB
50.621
5.054
27.058
30.77


619
GLU
CG
50.491
4.307
28.379
42.42


620
GLU
CD
50.541
2.833
28.160
86.17


621
GLU
OE1
51.464
2.282
27.586
100.00


622
GLU
OE2
49.454
2.226
28.584
100.00


623
GLU
N
52.506
7.246
27.649
30.68


624
GLU
CA
53.546
7.943
28.396
31.16


625
GLU
C
53.243
9.397
28.518
35.90


626
GLU
O
53.388
9.913
29.567
36.43


627
GLU
CB
54.865
7.737
27.681
33.02


628
GLU
CG
56.142
8.220
28.385
46.68


629
GLU
CD
57.242
8.086
27.353
78.67


630
GLU
OE1
57.023
7.823
26.163
59.52


631
GLU
OE2
58.437
8.258
27.835
84.75


632
ALA
N
52.800
10.068
27.441
34.48


633
ALA
CA
52.488
11.493
27.524
31.47


634
ALA
C
51.242
11.736
28.308
33.12


635
ALA
O
51.028
12.820
28.781
31.13


636
ALA
CB
52.294
12.082
26.132
31.22


637
GLN
N
50.354
10.764
28.383
32.47


638
GLN
CA
49.116
11.014
29.114
35.37


639
GLN
C
48.196
12.076
28.454
39.78


640
GLN
O
47.700
13.026
29.072
40.91


641
GLN
CB
49.434
11.386
30.560
39.09


642
GLN
CG
50.174
10.260
31.290
72.08


643
GLN
CD
49.157
9.374
31.957
100.00


644
GLN
OE1
48.700
9.687
33.092
100.00


645
GLN
NE2
48.738
8.341
31.206
99.83


646
ARG
N
47.979
11.913
27.140
28.50


647
ARG
CA
47.086
12.751
26.374
23.58


648
ARG
C
46.524
11.885
25.282
24.24


649
ARG
O
47.232
11.052
24.744
26.56


650
ARG
CB
47.779
13.904
25.722
23.27


651
ARG
CG
46.780
14.899
25.126
26.99


652
ARG
CD
47.361
16.299
24.960
26.70


653
ARG
NE
47.293
17.043
26.199
23.46


654
ARG
CZ
47.954
18.135
26.422
24.69


655
ARG
NH1
48.785
18.663
25.532
22.83


656
ARG
NH2
47.826
18.721
27.596
23.63


657
SER
N
45.249
12.005
25.019
19.60


658
SER
CA
44.632
11.302
23.912
18.87


659
SER
C
44.089
12.361
22.960
23.27


660
SER
O
43.869
13.515
23.332
20.11


661
SER
CB
43.455
10.478
24.343
21.80


662
SER
OG
43.930
9.552
25.250
30.13


663
TYR
N
43.820
11.959
21.724
21.22


664
TYR
CA
43.211
12.812
20.702
17.17


665
TYR
C
42.381
11.892
19.853
21.01


666
TYR
O
42.734
10.702
19.695
20.98


667
TYR
CB
44.261
13.337
19.707
18.74


668
TYR
CG
45.522
13.929
20.298
16.73


669
TYR
CD1
46.618
13.125
20.576
17.39


670
TYR
CD2
45.619
15.309
20.511
16.87


671
TYR
CE1
47.790
13.694
21.079
18.92


672
TYR
CE2
46.773
15.899
21.033
17.15


673
TYR
CZ
47.854
15.067
21.332
23.78


674
TYR
OH
49.001
15.602
21.876
23.03


675
ILE
N
41.328
12.435
19.274
17.07


676
ILE
CA
40.554
11.723
18.279
16.38


677
ILE
C
40.866
12.407
16.961
19.66


678
ILE
O
40.778
13.628
16.850
19.42


679
ILE
CB
39.027
11.735
18.509
21.59


680
ILE
CG1
38.653
10.894
19.775
21.73


681
ILE
CG2
38.255
11.292
17.209
19.23


682
ILE
CD1
37.204
11.104
20.239
19.35


683
LEU
N
41.336
11.645
16.006
15.32


684
LEU
CA
41.675
12.234
14.715
14.26


685
LEU
C
40.656
11.756
13.748
18.37


686
LEU
O
40.389
10.571
13.738
16.49


687
LEU
CB
43.066
11.848
14.198
13.33


688
LEU
CG
44.175
12.803
14.642
17.41


689
LEU
CD1
45.534
12.403
13.995
16.26


690
LEU
CD2
44.281
12.897
16.182
15.86


691
THR
N
40.050
12.645
12.963
14.18


692
THR
CA
39.024
12.145
12.076
13.33


693
THR
C
39.116
12.910
10.755
16.62


694
THR
O
39.788
13.946
10.696
15.02


695
THR
CB
37.644
12.338
12.815
15.01


696
THR
OG1
36.550
11.816
12.090
15.33


697
THR
CG2
37.396
13.829
13.035
11.94


698
GLN
N
38.432
12.417
9.692
15.62


699
GLN
CA
38.460
13.162
8.437
14.08


700
GLN
C
37.474
14.358
8.490
16.44


701
GLN
O
36.541
14.444
9.358
16.22


702
GLN
CB
38.017
12.224
7.323
13.86


703
GLN
CG
36.562
11.804
7.547
18.12


704
GLN
CD
35.915
10.847
6.544
19.07


705
GLN
OE1
34.655
10.690
6.513
19.98


706
GLN
NE2
36.756
10.142
5.818
11.61


707
GLY
N
37.556
15.222
7.487
15.42


708
GLY
CA
36.598
16.340
7.384
12.58


709
GLY
C
35.252
15.724
7.143
16.22


710
GLY
O
35.067
14.965
6.204
14.03


711
PRO
N
34.274
16.005
7.986
16.60


712
PRO
CA
32.950
15.389
7.745
15.78


713
PRO
C
32.405
15.529
6.317
20.52


714
PRO
O
32.677
16.525
5.642
19.37


715
PRO
CB
32.010
16.071
8.734
15.66


716
PRO
CG
32.902
16.749
9.800
17.67


717
PRO
CD
34.316
16.772
9.281
14.44


718
LEU
N
31.620
14.505
5.898
16.55


719
LEU
CA
30.962
14.416
4.631
14.43


720
LEU
C
29.522
14.909
4.834
22.58


721
LEU
O
29.029
14.985
5.933
20.15


722
LEU
CB
30.952
12.997
4.038
14.77


723
LEU
CG
32.352
12.481
3.728
18.92


724
LEU
CD1
32.333
10.957
3.798
20.45


725
LEU
CD2
32.799
12.968
2.329
19.10


726
PRO
N
28.852
15.291
3.742
23.61


727
PRO
CA
27.526
15.812
3.867
23.49


728
PRO
C
26.616
14.852
4.520
26.41


729
PRO
O
25.574
15.258
4.934
30.17


730
PRO
CB
27.017
16.030
2.454
25.04


731
PRO
CG
28.057
15.523
1.480
29.04


732
PRO
CD
29.290
15.276
2.312
23.33


733
ASN
N
26.973
13.586
4.607
21.62


734
ASN
CA
26.068
12.632
5.237
17.84


735
ASN
C
26.608
12.193
6.557
22.95


736
ASN
O
25.978
11.361
7.233
23.70


737
ASN
CB
25.861
11.386
4.362
18.60


738
ASN
CG
27.174
10.691
3.998
24.49


739
ASN
OD1
28.160
11.365
3.684
24.35


740
ASN
ND2
27.214
9.338
4.017
24.03


741
THR
N
27.791
12.714
6.939
16.40


742
THR
CA
28.325
12.237
8.220
15.19


743
THR
C
28.433
13.364
9.223
21.17


744
THR
O
29.095
13.234
10.219
19.70


745
THR
CB
29.694
11.529
8.112
18.74


746
THR
OG1
30.690
12.447
7.709
19.88


747
THR
CG2
29.683
10.379
7.103
16.93


748
CYS
N
27.783
14.491
8.970
16.82


749
CYS
CA
27.883
15.573
9.943
18.20


750
CYS
C
27.174
15.247
11.228
19.02


751
CYS
O
27.613
15.697
12.308
20.16


752
CYS
CB
27.325
16.925
9.410
19.21


753
CYS
SG
28.252
17.458
7.951
23.17


754
GLY
N
26.054
14.501
11.125
17.59


755
GLY
CA
25.352
14.185
12.370
16.40


756
GLY
C
26.210
13.222
13.189
18.70


757
GLY
O
26.279
13.293
14.394
18.52


758
HIS
N
26.865
12.306
12.499
17.15


759
HIS
CA
27.754
11.319
13.158
17.16


760
HIS
C
28.925
12.017
13.833
20.07


761
HIS
O
29.404
11.647
14.889
20.41


762
HIS
CB
28.393
10.342
12.120
18.16


763
HIS
CG
27.384
9.635
11.299
19.12


764
HIS
ND1
27.704
9.228
9.989
22.15


765
HIS
CD2
26.096
9.300
11.596
17.48


766
HIS
CE1
26.596
8.639
9.509
20.83


767
HIS
NE2
25.620
8.661
10.438
20.03


768
PHE
N
29.491
13.003
13.166
17.15


769
PHE
CA
30.592
13.729
13.736
15.25


770
PHE
C
30.214
14.331
15.139
22.13


771
PHE
O
30.894
14.098
16.171
21.51


772
PHE
CB
31.025
14.822
12.736
15.12


773
PHE
CG
32.096
15.740
13.307
14.74


774
PHE
CD1
31.746
16.887
14.020
15.97


775
PHE
CD2
33.466
15.466
13.140
15.95


776
PHE
CE1
32.734
17.739
14.539
16.67


777
PHE
CE2
34.475
16.298
13.663
17.69


778
PHE
CZ
34.095
17.428
14.398
14.91


779
TRP
N
29.096
15.088
15.168
19.55


780
TRP
CA
28.632
15.704
16.421
18.79


781
TRP
C
28.147
14.656
17.418
21.85


782
TRP
O
28.289
14.839
18.633
21.13


783
TRP
CB
27.576
16.758
16.169
16.67


784
TRP
CG
28.210
17.904
15.491
16.11


785
TRP
CD1
27.962
18.318
14.214
18.99


786
TRP
CD2
29.206
18.776
16.023
14.97


787
TRP
NE1
28.768
19.412
13.916
18.96


788
TRP
CE2
29.547
19.692
15.015
18.62


789
TRP
CE3
29.867
18.880
17.250
16.41


790
TRP
CZ2
30.506
20.686
15.213
17.94


791
TRP
CZ3
30.823
19.869
17.428
16.16


792
TRP
CH2
31.165
20.737
16.412
16.86


793
GLU
N
27.626
13.536
16.911
17.79


794
GLU
CA
27.268
12.489
17.811
16.48


795
GLU
C
28.499
12.004
18.561
20.28


796
GLU
O
28.480
11.817
19.780
18.97


797
GLU
CB
26.630
11.293
17.103
17.70


798
GLU
CG
26.576
10.108
18.107
18.51


799
GLU
CD
25.985
8.904
17.457
36.95


800
GLU
OE1
25.635
8.939
16.304
24.52


801
GLU
OE2
25.828
7.845
18.231
22.85


802
MET
N
29.622
11.855
17.813
16.81


803
MET
CA
30.873
11.423
18.408
15.42


804
MET
C
31.414
12.466
19.451
21.03


805
MET
O
31.916
12.180
20.552
17.41


806
MET
CB
31.905
11.171
17.275
15.36


807
MET
CG
33.296
10.921
17.815
15.60


808
MET
SD
34.527
10.644
16.486
19.45


809
MET
CE
34.636
12.330
15.779
16.29


810
VAL
N
31.345
13.741
19.059
17.81


811
VAL
CA
31.809
14.761
19.961
15.34


812
VAL
C
31.027
14.648
21.239
20.80


813
VAL
O
31.512
14.740
22.361
21.08


814
VAL
CB
31.555
16.117
19.308
18.34


815
VAL
CG1
31.720
17.289
20.311
17.11


816
VAL
CG2
32.560
16.297
18.112
16.59


817
TRP
N
29.760
14.465
21.061
23.24


818
TRP
CA
28.891
14.345
22.223
25.45


819
TRP
C
29.223
13.143
23.061
25.99


820
TRP
O
29.403
13.249
24.269
25.20


821
TRP
CB
27.412
14.241
21.777
27.30


822
TRP
CG
26.523
14.219
22.984
30.45


823
TRP
CD1
26.111
13.118
23.651
33.52


824
TRP
CD2
25.979
15.340
23.673
31.02


825
TRP
NE1
25.370
13.477
24.740
33.46


826
TRP
CE2
25.283
14.838
24.787
36.13


827
TRP
CE3
26.031
16.723
23.459
35.07


828
TRP
CZ2
24.642
15.693
25.691
36.39


829
TRP
CZ3
25.390
17.583
24.335
37.49


830
TRP
CH2
24.716
17.061
25.452
38.40


831
GLU
N
29.254
11.979
22.430
20.77


832
GLU
CA
29.484
10.733
23.165
19.32


833
GLU
C
30.849
10.628
23.808
24.59


834
GLU
O
30.997
10.008
24.836
22.28


835
GLU
CB
29.255
9.492
22.281
20.24


836
GLU
CG
27.769
9.267
21.915
22.70


837
GLU
CD
27.538
8.382
20.721
31.58


838
GLU
OE1
28.422
7.828
20.071
28.77


839
GLU
OE2
26.263
8.280
20.456
22.97


840
GLN
N
31.853
11.228
23.201
19.41


841
GLN
CA
33.216
11.131
23.689
18.18


842
GLN
C
33.531
12.204
24.662
20.10


843
GLN
O
34.595
12.205
25.267
21.48


844
GLN
CB
34.246
11.110
22.532
18.95


845
GLN
CG
33.923
9.996
21.532
19.84


846
GLN
CD
33.991
8.651
22.246
39.40


847
GLN
CE1
34.851
8.438
23.105
28.56


848
GLN
NE2
33.079
7.739
21.948
26.05


849
LYS
N
32.598
13.105
24.794
19.33


850
LYS
CA
32.677
14.184
25.768
18.87


851
LYS
C
33.789
15.161
25.514
22.27


852
LYS
O
34.337
15.793
26.422
19.41


853
LYS
CB
32.735
13.639
27.188
21.88


854
LYS
CG
31.398
13.126
27.651
19.83


855
LYS
CD
31.426
12.036
28.700
45.14


856
LYS
CE
30.008
11.554
29.070
76.91


857
LYS
NZ
29.545
10.345
28.337
96.48


858
SER
N
34.066
15.353
24.244
20.79


859
SER
CA
35.092
16.316
23.892
17.81


860
SER
C
34.624
17.729
24.205
21.92


861
SER
O
33.428
18.054
24.168
21.51


862
SER
CB
35.467
16.186
22.410
19.18


863
SER
OG
35.724
14.822
22.082
17.75


864
ARG
N
35.604
18.554
24.504
17.92


865
ARG
CA
35.383
19.949
24.807
16.44


866
ARG
C
35.798
20.801
23.627
19.96


867
ARG
O
35.360
21.920
23.437
19.40


868
ARG
CB
36.288
20.356
25.943
18.45


869
ARG
CG
35.931
21.718
26.512
32.13


870
ARG
CD
36.767
22.844
26.008
47.45


871
ARG
NE
36.397
24.110
26.645
78.03


872
ARG
CZ
35.147
24.537
26.840
72.70


873
ARG
NH1
34.080
23.841
26.491
57.33


874
ARG
NH2
34.975
25.713
27.412
58.72


875
GLY
N
36.733
20.313
22.843
18.99


876
GLY
CA
37.197
21.150
21.735
17.48


877
GLY
C
37.354
20.376
20.447
20.79


878
GLY
O
37.564
19.146
20.464
17.85


879
VAL
N
37.263
21.126
19.331
16.59


880
VAL
CA
37.432
20.590
17.992
13.96


881
VAL
C
38.479
21.445
17.339
19.19


882
VAL
O
38.287
22.668
17.275
20.97


883
VAL
CB
36.129
20.735
17.192
15.20


884
VAL
CG1
36.421
20.354
15.742
14.08


885
VAL
CG2
35.021
19.821
17.752
15.12


886
VAL
N
39.576
20.856
16.870
13.97


887
VAL
CA
40.603
21.610
16.157
11.79


888
VAL
C
40.457
21.284
14.648
18.77


889
VAL
O
40.570
20.121
14.232
18.28


890
VAL
CB
41.958
21.180
16.675
12.96


891
VAL
CG1
43.076
21.854
15.888
14.53


892
VAL
CG2
42.053
21.591
18.138
13.41


893
MET
N
40.169
22.317
13.833
17.03


894
MET
CA
40.019
22.225
12.360
15.40


895
MET
C
41.205
22.846
11.677
18.09


896
MET
O
41.430
24.034
11.821
19.11


897
MET
CB
38.727
22.916
11.923
14.55


898
MET
CG
38.502
22.833
10.454
15.42


899
MET
SD
36.823
23.344
10.018
19.36


900
MET
CE
36.836
23.095
8.223
17.20


901
LEU
N
41.979
22.048
10.954
10.88


902
LEU
CA
43.193
22.584
10.379
10.33


903
LEU
C
43.143
22.854
8.877
13.92


904
LEU
O
44.145
23.245
8.271
14.65


905
LEU
CB
44.326
21.595
10.679
13.36


906
LEU
CG
44.519
21.273
12.178
16.29


907
LEU
CD1
45.594
20.155
12.274
14.38


908
LEU
CD2
45.006
22.542
12.913
13.63


909
ASN
N
41.968
22.712
8.311
13.55


910
ASN
CA
41.826
22.925
6.905
17.04


911
ASN
C
40.701
23.897
6.601
18.91


912
ASN
O
39.965
24.258
7.509
17.09


913
ASN
CB
41.343
21.584
6.310
18.53


914
ASN
CG
39.949
21.183
6.753
18.64


915
ASN
OD1
38.953
21.213
5.995
19.54


916
ASN
ND2
39.867
20.701
7.964
12.69


917
ARG
N
40.583
24.340
5.325
16.20


918
ARG
CA
39.429
25.199
4.934
18.31


919
ARG
C
38.419
24.316
4.226
23.61


920
ARG
O
38.770
23.219
3.769
20.22


921
ARG
CB
39.765
26.336
3.973
19.06


922
ARG
CG
40.782
27.259
4.610
27.14


923
ARG
CD
40.998
28.568
3.854
35.02


924
ARG
NE
41.400
28.489
2.457
76.50


925
ARG
CZ
42.181
27.557
1.889
100.00


926
ARG
NH1
42.629
26.485
2.605
100.00


927
ARG
NH2
42.425
27.679
0.574
74.39


928
VAL
N
37.162
24.772
4.126
17.39


929
VAL
CA
36.162
23.961
3.451
18.47


930
VAL
C
36.529
23.752
1.972
24.72


931
VAL
O
36.433
22.657
1.424
20.57


932
VAL
CB
34.781
24.569
3.651
20.83


933
VAL
CG1
33.815
24.070
2.560
18.89


934
VAL
CG2
34.319
24.222
5.084
18.54


935
MET
N
37.039
24.816
1.331
21.78


936
MET
CA
37.494
24.680
−0.054
22.02


937
MET
C
39.008
24.831
−0.154
23.31


938
MET
O
39.563
25.775
0.348
21.11


939
MET
CB
36.915
25.735
−0.970
24.02


940
MET
CG
37.613
25.464
−2.292
33.60


941
MET
SD
36.695
26.151
−3.672
42.56


942
MET
CE
35.122
25.238
−3.576
37.18


943
GLU
N
39.697
23.938
−0.824
18.74


944
GLU
CA
41.128
24.062
−0.945
18.84


945
GLU
C
41.474
23.440
−2.263
26.07


946
GLU
O
40.841
22.451
−2.688
29.43


947
GLU
CB
41.877
23.271
0.166
21.64


948
GLU
CG
41.562
23.754
1.595
24.84


949
GLU
CD
42.242
22.902
2.628
27.45


950
GLU
OE1
42.453
21.723
2.501
25.26


951
GLU
OE2
42.525
23.545
3.714
24.68


952
LYS
N
42.458
24.000
−2.901
22.86


953
LYS
CA
42.899
23.487
−4.187
23.50


954
LYS
C
41.742
23.348
−5.204
29.15


955
LYS
O
41.767
22.481
−6.061
30.13


956
LYS
CB
43.790
22.226
−4.009
26.67


957
LYS
CG
45.143
22.628
−3.333
33.73


958
LYS
CD
46.022
21.518
−2.773
52.09


959
LYS
CE
47.424
22.009
−2.422
39.14


960
LYS
NZ
48.324
22.031
−3.581
76.66


961
GLY
N
40.695
24.167
−5.076
23.79


962
GLY
CA
39.609
24.073
−6.010
21.74


963
GLY
C
38.631
23.039
−5.693
24.19


964
GLY
O
37.690
22.826
−6.457
29.23


965
SER
N
38.860
22.368
−4.620
16.90


966
SER
CA
37.939
21.336
−4.250
19.52


967
SER
C
37.336
21.506
−2.901
22.34


968
SER
O
37.870
22.237
−2.070
20.15


969
SER
CB
38.620
20.006
−4.177
25.21


970
SER
OG
38.845
19.720
−5.538
47.69


971
LEU
N
36.239
20.761
−2.693
15.65


972
LEU
CA
35.596
20.819
−1.374
14.31


973
LEU
C
36.183
19.731
−0.502
21.78


974
LEU
O
35.871
18.558
−0.677
26.91


975
LEU
CB
34.104
20.610
−1.481
15.29


976
LEU
CG
33.470
21.756
−2.283
21.97


977
LEU
CD1
31.980
21.527
−2.467
21.98


978
LEU
CD2
33.677
23.043
−1.468
26.21


979
LYS
N
37.037
20.122
0.436
17.45


980
LYS
CA
37.741
19.191
1.299
14.44


981
LYS
C
37.009
18.778
2.566
17.63


982
LYS
O
37.488
17.920
3.313
16.36


983
LYS
CB
39.043
19.830
1.755
14.89


984
LYS
CG
39.990
20.179
0.609
20.49


985
LYS
CD
40.109
19.031
−0.365
21.67


986
LYS
CE
41.374
18.235
−0.210
30.52


987
LYS
NZ
41.699
17.355
−1.379
24.68


988
CYS
N
35.889
19.384
2.848
16.47


989
CYS
CA
35.155
19.078
4.070
16.96


990
CYS
C
33.741
19.677
3.961
19.21


991
CYS
O
33.563
20.642
3.244
18.82


992
CYS
CB
35.948
19.897
5.159
16.39


993
CYS
SG
35.331
19.703
6.887
18.71


994
ALA
N
32.760
19.154
4.700
16.15


995
ALA
CA
31.415
19.714
4.739
14.64


996
ALA
C
31.396
20.957
5.690
19.23


997
ALA
O
32.233
21.145
6.585
17.35


998
ALA
CB
30.467
18.651
5.231
13.19


999
GLN
N
30.461
21.869
5.475
21.44


1000
GLN
CA
30.365
23.045
6.336
24.00


1001
GLN
C
29.591
22.536
7.463
24.84


1002
GLN
O
28.375
22.686
7.394
24.39


1003
GLN
CB
29.530
24.166
5.663
26.72


1004
GLN
CG
29.391
25.440
6.544
22.81


1005
GLN
CD
30.676
25.983
7.104
25.37


1006
GLN
OE1
30.793
26.198
8.315
30.89


1007
GLN
NE2
31.616
26.296
6.240
21.26


1008
TYR
N
30.266
21.838
8.409
17.99


1009
TYR
CA
29.535
21.156
9.487
15.44


1010
TYR
C
29.151
21.957
10.748
22.11


1011
TYR
O
28.643
21.358
11.740
18.91


1012
TYR
CB
30.286
19.866
9.883
16.63


1013
TYR
CG
31.599
20.198
10.522
17.61


1014
TYR
CD1
32.752
20.328
9.749
16.52


1015
TYR
CD2
31.683
20.328
11.910
15.79


1016
TYR
CE1
33.967
20.657
10.340
15.78


1017
TYR
CE2
32.904
20.620
12.511
12.70


1018
TYR
CZ
34.026
20.821
11.722
18.43


1019
TYR
OH
35.226
21.088
12.310
18.28


1020
TRP
N
29.389
23.282
10.739
19.64


1021
TRP
CA
29.017
24.082
11.885
20.07


1022
TRP
C
28.335
25.344
11.398
20.86


1023
TRP
O
28.609
25.785
10.296
18.14


1024
TRP
CB
30.276
24.405
12.737
19.79


1025
TRP
CG
31.146
25.427
12.111
20.56


1026
TRP
CD1
31.114
26.769
12.391
23.88


1027
TRP
CD2
32.177
25.255
11.089
19.89


1028
TRP
NE1
32.061
27.448
11.631
23.47


1029
TRP
CE2
32.720
26.554
10.813
23.19


1030
TRP
CE3
32.680
24.162
10.363
21.33


1031
TRP
CZ2
33.724
26.765
9.888
21.55


1032
TRP
CZ3
33.681
24.396
9.418
21.71


1033
TRP
CH2
34.190
25.681
9.187
22.67


1034
PRO
N
27.472
25.933
12.244
19.83


1035
PRO
CA
26.755
27.155
11.892
19.59


1036
PRO
C
27.657
28.375
11.800
23.09


1037
PRO
O
28.534
28.630
12.627
24.72


1038
PRO
CB
25.736
27.390
13.013
20.41


1039
PRO
CG
26.142
26.514
14.203
24.23


1040
PRO
CD
27.223
25.561
13.671
19.47


1041
GLN
N
27.361
29.188
10.787
20.72


1042
GLN
CA
28.094
30.394
10.583
24.35


1043
GLN
C
27.360
31.604
11.131
30.18


1044
GLN
O
27.958
32.680
11.285
28.65


1045
GLN
CB
28.440
30.572
9.138
25.68


1046
GLN
CG
29.324
29.390
8.712
36.40


1047
GLN
CD
29.769
29.566
7.304
56.84


1048
GLN
OE1
28.981
29.299
6.359
45.16


1049
GLN
NE2
30.999
30.080
7.175
51.88


1050
LYS
N
26.094
31.422
11.446
24.00


1051
LYS
CA
25.374
32.529
12.050
23.16


1052
LYS
C
24.547
32.118
13.199
19.74


1053
LYS
O
23.907
31.078
13.158
22.04


1054
LYS
CB
24.653
33.411
11.123
28.65


1055
LYS
CG
23.416
32.791
10.569
74.23


1056
LYS
CD
23.256
33.389
9.195
100.00


1057
LYS
CE
24.577
33.985
8.716
100.00


1058
LYS
NZ
25.063
33.363
7.463
100.00


1059
GLU
N
24.612
32.988
14.210
19.68


1060
GLU
CA
23.924
32.760
15.437
18.75


1061
GLU
C
22.542
32.373
15.160
22.72


1062
GLU
O
22.083
31.334
15.615
21.78


1063
GLU
CB
23.897
34.027
16.333
20.49


1064
GLU
CG
25.250
34.370
17.051
17.63


1065
GLU
CD
26.224
35.178
16.201
22.34


1066
GLU
OE1
26.156
35.277
14.996
23.40


1067
GLU
OE2
27.088
35.835
16.877
20.11


1068
GLU
N
21.820
33.237
14.433
18.53


1069
GLU
CA
20.418
32.935
14.214
19.99


1070
GLU
C
20.107
31.763
13.281
27.09


1071
GLU
O
18.937
31.405
13.088
23.53


1072
GLU
CB
19.614
34.172
13.817
20.56


1073
GLU
CG
20.050
34.671
12.449
21.72


1074
GLU
CD
21.264
35.493
12.560
32.26


1075
GLU
OE1
22.170
35.239
13.292
30.85


1076
GLU
OE2
21.209
36.560
11.870
46.23


1077
LYS
N
21.136
31.153
12.687
24.09


1078
LYS
CA
20.821
30.032
11.815
25.40


1079
LYS
C
21.462
28.780
12.346
32.06


1080
LYS
O
22.539
28.413
11.875
34.08


1081
LYS
CB
21.378
30.287
10.448
25.92


1082
LYS
CG
20.579
31.355
9.738
53.04


1083
LYS
CD
20.028
30.875
8.415
61.11


1084
LYS
CE
18.577
30.432
8.487
81.13


1085
LYS
NZ
18.161
29.607
7.339
100.00


1086
GLU
N
20.846
28.148
13.337
24.74


1087
GLU
CA
21.437
26.950
13.921
24.02


1088
GLU
C
21.324
25.780
12.983
28.33


1089
GLU
O
20.606
25.824
12.017
25.06


1090
GLU
CB
20.762
26.410
15.183
25.15


1091
GLU
CG
19.726
27.239
15.866
51.90


1092
GLU
CD
18.497
27.376
15.063
40.35


1093
GLU
OE1
17.593
26.572
15.036
36.72


1094
GLU
OE2
18.492
28.538
14.496
33.99


1095
MET
N
21.986
24.679
13.350
24.61


1096
MET
CA
21.950
23.455
12.553
21.48


1097
MET
C
21.326
22.368
13.373
27.14


1098
MET
O
21.641
22.217
14.572
26.22


1099
MET
CB
23.369
22.980
12.072
21.43


1100
MET
CG
23.958
23.895
11.019
22.29


1101
MET
SD
25.666
23.460
10.592
26.20


1102
MET
CE
25.256
22.169
9.435
23.94


1103
ILE
N
20.444
21.594
12.707
27.52


1104
ILE
CA
19.811
20.472
13.387
28.07


1105
ILE
C
20.179
19.186
12.668
32.13


1106
ILE
O
20.079
19.113
11.435
30.18


1107
ILE
CB
18.293
20.602
13.485
32.74


1108
ILE
CG1
17.977
21.495
14.686
32.67


1109
ILE
CG2
17.799
19.197
13.784
32.86


1110
ILE
CD1
16.777
22.374
14.453
40.14


1111
PHE
N
20.657
18.208
13.416
23.83


1112
PHE
CA
21.041
16.959
12.785
23.10


1113
PHE
C
19.998
15.956
13.154
25.20


1114
PHE
O
20.027
15.383
14.223
23.48


1115
PHE
CB
22.477
16.491
13.147
22.44


1116
PHE
CG
23.457
17.603
12.869
21.09


1117
PHE
CD1
23.901
17.863
11.574
21.96


1118
PHE
CD2
23.914
18.415
13.901
20.96


1119
PHE
CE1
24.802
18.889
11.307
19.88


1120
PHE
CE2
24.819
19.449
13.666
21.74


1121
PHE
CZ
25.240
19.692
12.360
18.52


1122
GLU
N
19.041
15.794
12.276
26.50


1123
GLU
CA
17.949
14.903
12.589
27.86


1124
GLU
C
18.330
13.470
12.781
32.08


1125
GLU
O
17.727
12.809
13.608
35.43


1126
GLU
CB
16.877
14.981
11.517
30.62


1127
GLU
CG
16.580
16.453
11.155
62.94


1128
GLU
CD
15.389
16.595
10.252
100.00


1129
GLU
OE1
15.483
16.977
9.084
100.00


1130
GLU
OE2
14.265
16.211
10.846
100.00


1131
ASP
N
19.299
12.959
12.012
25.73


1132
ASP
CA
19.656
11.567
12.181
23.02


1133
ASP
C
20.185
11.281
13.545
28.07


1134
ASP
O
19.956
10.200
14.084
29.11


1135
ASP
CB
20.632
11.086
11.107
25.54


1136
ASP
CG
21.905
11.885
11.021
37.00


1137
ASP
OD1
22.084
12.993
11.515
30.66


1138
ASP
OD2
22.789
11.248
10.330
34.51


1139
THR
N
20.935
12.242
14.102
22.93


1140
THR
CA
21.496
12.004
15.402
20.67


1141
THR
C
20.850
12.755
16.525
23.97


1142
THR
O
21.319
12.650
17.645
24.14


1143
THR
CB
23.011
12.160
15.438
24.59


1144
THR
OG1
23.323
13.466
15.015
22.89


1145
THR
CG2
23.629
11.120
14.521
20.72


1146
ASN
N
19.789
13.480
16.239
25.41


1147
ASN
CA
19.071
14.191
17.312
27.59


1148
ASN
C
19.850
15.245
18.085
29.45


1149
ASN
O
19.714
15.298
19.304
27.48


1150
ASN
CB
18.408
13.208
18.326
36.52


1151
ASN
CG
17.000
13.621
18.723
67.20


1152
ASN
OD1
16.346
14.422
18.030
53.22


1153
ASN
ND2
16.539
13.115
19.867
60.40


1154
LEU
N
20.633
16.084
17.377
24.61


1155
LEU
CA
21.440
17.164
17.988
23.07


1156
LEU
C
21.206
18.521
17.335
26.63


1157
LEU
O
21.001
18.634
16.126
23.32


1158
LEU
CB
22.937
16.857
17.853
21.58


1159
LEU
CG
23.337
15.645
18.637
25.34


1160
LEU
CD1
24.640
15.072
18.051
25.68


1161
LEU
CD2
23.514
16.058
20.088
25.96


1162
LYS
N
21.305
19.557
18.160
23.08


1163
LYS
CA
21.182
20.874
17.655
21.49


1164
LYS
C
22.505
21.524
17.940
22.10


1165
LYS
O
23.066
21.305
18.982
23.53


1166
LYS
CB
20.067
21.662
18.336
21.09


1167
LYS
CG
19.870
23.030
17.657
21.83


1168
LYS
CD
18.540
23.701
18.050
20.42


1169
LYS
CE
18.579
24.236
19.482
27.34


1170
LYS
NZ
17.233
24.626
19.969
28.39


1171
LEU
N
22.992
22.343
17.032
21.33


1172
LEU
CA
24.283
22.965
17.219
21.43


1173
LEU
C
24.163
24.452
16.940
23.20


1174
LEU
O
23.767
24.857
15.847
23.59


1175
LEU
CB
25.209
22.322
16.142
22.80


1176
LEU
CG
26.646
22.855
16.136
23.00


1177
LEU
CD1
27.324
22.527
17.442
20.39


1178
LEU
CD2
27.437
22.271
14.965
24.15


1179
THR
N
24.498
25.276
17.874
20.33


1180
THR
CA
24.330
26.697
17.621
20.96


1181
THR
C
25.596
27.533
17.770
20.29


1182
THR
O
26.356
27.291
18.686
22.10


1183
THR
CB
23.364
27.260
18.679
21.96


1184
THR
OG1
22.155
26.543
18.666
22.75


1185
THR
CG2
23.137
28.739
18.365
21.55


1186
LEU
N
25.777
28.540
16.915
16.73


1187
LEU
CA
26.914
29.399
17.070
17.12


1188
LEU
C
26.594
30.412
18.199
25.18


1189
LEU
O
25.599
31.140
18.144
21.33


1190
LEU
CB
27.158
30.194
15.745
18.33


1191
LEU
CG
28.269
31.272
15.781
22.75


1192
LEU
CD1
29.625
30.638
16.105
25.53


1193
LEU
CD2
28.418
31.874
14.386
20.81


1194
ILE
N
27.430
30.433
19.251
22.62


1195
ILE
CA
27.231
31.325
20.365
18.73


1196
ILE
C
28.105
32.558
20.189
25.51


1197
ILE
O
27.689
33.684
20.405
24.71


1198
ILE
CB
27.524
30.585
21.640
17.81


1199
ILE
CG1
26.543
29.420
21.797
17.68


1200
ILE
CG2
27.447
31.544
22.811
19.05


1201
ILE
CD1
25.088
29.851
21.734
20.62


1202
SER
N
29.319
32.399
19.729
20.59


1203
SER
CA
30.136
33.576
19.528
22.30


1204
SER
C
31.333
33.201
18.738
28.89


1205
SER
O
31.682
32.043
18.682
27.38


1206
SER
CB
30.663
34.191
20.812
28.97


1207
SER
OG
31.304
33.178
21.542
43.41


1208
GLU
N
31.978
34.183
18.172
28.09


1209
GLU
CA
33.164
33.904
17.391
31.06


1210
GLU
C
34.245
34.958
17.494
36.63


1211
GLU
O
33.982
36.166
17.532
39.50


1212
GLU
CB
32.762
33.570
15.962
33.57


1213
GLU
CG
33.016
34.695
14.975
57.41


1214
GLU
CD
32.296
34.494
13.672
87.92


1215
GLU
OE1
32.149
33.405
13.128
58.92


1216
GLU
OE2
31.820
35.627
13.204
100.00


1217
ASP
N
35.473
34.500
17.545
25.81


1218
ASP
CA
36.614
35.390
17.665
25.56


1219
ASP
C
37.560
35.177
16.468
33.25


1220
ASP
O
38.298
34.191
16.394
31.20


1221
ASP
CB
37.249
35.034
19.028
29.04


1222
ASP
CG
38.528
35.708
19.390
43.28


1223
ASP
OD1
38.845
36.806
18.949
44.46


1224
ASP
OD2
39.272
34.945
20.175
48.31


1225
ILE
N
37.495
36.089
15.490
30.26


1226
ILE
CA
38.260
36.014
14.247
30.37


1227
ILE
C
39.612
36.677
14.347
31.11


1228
ILE
O
39.742
37.831
14.692
31.83


1229
ILE
CB
37.472
36.612
13.070
34.71


1230
ILE
CG1
36.091
35.991
12.955
36.33


1231
ILE
CG2
38.216
36.607
11.722
35.66


1232
ILE
CD1
34.977
36.984
13.317
65.27


1233
LYS
N
40.627
35.937
14.049
22.86


1234
LYS
CA
41.961
36.472
14.069
23.68


1235
LYS
C
42.448
36.470
12.610
25.39


1236
LYS
O
41.705
36.091
11.707
25.60


1237
LYS
CB
42.921
35.769
15.050
24.58


1238
LYS
CG
42.498
35.848
16.530
30.43


1239
LYS
CD
42.894
37.206
17.140
56.04


1240
LYS
CE
42.275
37.473
18.509
77.38


1241
LYS
NZ
43.040
38.439
19.321
100.00


1242
THR
N
43.669
36.907
12.395
22.88


1243
THR
CA
44.215
36.986
11.049
23.70


1244
THR
C
44.240
35.654
10.392
30.85


1245
THR
O
43.898
35.565
9.210
34.77


1246
THR
CB
45.696
37.481
10.942
30.00


1247
THR
OG1
46.602
36.842
11.798
35.80


1248
THR
CG2
45.878
38.989
10.992
61.05


1249
TYR
N
44.743
34.649
11.108
21.60


1250
TYR
CA
44.882
33.376
10.456
18.56


1251
TYR
C
44.143
32.244
11.082
25.54


1252
TYR
O
44.324
31.078
10.663
28.06


1253
TYR
CB
46.334
33.048
10.304
18.65


1254
TYR
CG
46.986
32.802
11.597
20.73


1255
TYR
CD1
47.329
33.853
12.463
21.11


1256
TYR
CD2
47.327
31.498
11.937
20.37


1257
TYR
CE1
48.003
33.584
13.661
20.41


1258
TYR
CE2
47.992
31.216
13.130
21.74


1259
TYR
CZ
48.327
32.257
13.994
29.63


1260
TYR
OH
49.006
31.917
15.159
23.15


1261
TYR
N
43.337
32.562
12.101
21.11


1262
TYR
CA
42.551
31.528
12.759
22.22


1263
TYR
C
41.350
32.139
13.375
24.48


1264
TYR
O
41.326
33.342
13.534
23.41


1265
TYR
CB
43.342
30.705
13.792
23.10


1266
TYR
CG
43.742
31.476
15.028
22.92


1267
TYR
CD1
44.930
32.194
15.073
20.83


1268
TYR
CD2
42.959
31.415
16.177
24.45


1269
TYR
CE1
45.287
32.851
16.247
21.19


1270
TYR
CE2
43.297
32.082
17.354
21.53


1271
TYR
CZ
44.483
32.785
17.378
21.56


1272
TYR
OH
44.815
33.471
18.512
22.47


1273
THR
N
40.369
31.311
13.688
20.51


1274
THR
CA
39.136
31.768
14.317
20.65


1275
THR
C
38.791
30.762
15.378
25.40


1276
THR
O
38.905
29.535
15.158
21.46


1277
THR
CB
37.933
31.848
13.303
25.48


1278
THR
OG1
38.230
32.801
12.320
23.97


1279
THR
CG2
36.650
32.293
13.969
17.96


1280
VAL
N
38.318
31.309
16.488
19.73


1281
VAL
CA
37.851
30.530
17.623
17.86


1282
VAL
C
36.371
30.790
17.799
23.43


1283
VAL
O
35.931
31.937
17.908
23.75


1284
VAL
CB
38.557
30.926
18.924
22.90


1285
VAL
CG1
38.176
29.946
20.012
23.85


1286
VAL
CG2
40.057
30.808
18.737
23.85


1287
ARG
N
35.609
29.713
17.805
20.09


1288
ARG
CA
34.172
29.781
17.953
19.44


1289
ARG
C
33.699
29.002
19.174
23.12


1290
ARG
O
34.205
27.901
19.557
20.13


1291
ARG
CB
33.431
29.182
16.745
16.93


1292
ARG
CG
33.792
29.938
15.473
24.10


1293
ARG
CD
33.027
29.483
14.215
26.79


1294
ARG
NE
33.620
30.035
12.964
35.76


1295
ARG
CZ
34.769
29.584
12.421
51.01


1296
ARG
NH1
35.509
28.558
12.930
52.65


1297
ARG
NH2
35.199
30.195
11.337
44.38


1298
GLN
N
32.711
29.625
19.799
16.92


1299
GLN
CA
32.040
28.948
20.858
20.12


1300
GLN
C
30.679
28.456
20.290
23.98


1301
GLN
O
29.851
29.207
19.711
23.75


1302
GLN
CB
31.889
29.796
22.106
23.97


1303
GLN
CG
31.076
29.015
23.134
41.20


1304
GLN
CD
30.559
29.958
24.176
67.03


1305
GLN
OE1
31.089
31.100
24.332
52.88


1306
GLN
NE2
29.502
29.485
24.841
56.56


1307
LEU
N
30.494
27.148
20.356
17.61


1308
LEU
CA
29.310
26.552
19.806
18.88


1309
LEU
C
28.563
25.874
20.920
26.36


1310
LEU
O
29.175
25.420
21.914
29.37


1311
LEU
CB
29.714
25.412
18.853
19.47


1312
LEU
CG
30.632
25.859
17.719
24.78


1313
LEU
CD1
31.236
24.593
17.132
23.14


1314
LEU
CD2
29.825
26.634
16.632
19.35


1315
GLU
N
27.268
25.770
20.753
20.30


1316
GLU
CA
26.490
25.073
21.753
19.19


1317
GLU
C
25.861
23.866
21.128
23.29


1318
GLU
O
25.154
23.934
20.078
25.61


1319
GLU
CB
25.419
25.931
22.471
22.13


1320
GLU
CG
24.553
25.130
23.502
24.76


1321
GLU
CD
23.408
26.017
23.909
45.63


1322
GLU
OE1
23.525
26.834
24.760
51.61


1323
GLU
OE2
22.343
25.925
23.137
62.26


1324
LEU
N
26.125
22.751
21.814
21.06


1325
LEU
CA
25.635
21.497
21.378
22.31


1326
LEU
C
24.546
21.016
22.327
27.67


1327
LEU
O
24.761
20.942
23.522
26.01


1328
LEU
CB
26.852
20.528
21.268
24.03


1329
LEU
CG
26.539
19.163
20.645
23.92


1330
LEU
CD1
26.152
19.220
19.149
20.97


1331
LEU
CD2
27.784
18.312
20.815
23.65


1332
GLU
N
23.403
20.711
21.735
25.02


1333
GLU
CA
22.302
20.214
22.466
26.18


1334
GLU
C
21.791
18.886
21.998
33.77


1335
GLU
O
21.443
18.671
20.844
34.24


1336
GLU
CB
21.070
21.145
22.382
28.09


1337
GLU
CG
19.918
20.621
23.287
31.05


1338
GLU
CD
18.778
21.580
23.311
37.23


1339
GLU
OE1
18.856
22.616
22.768
35.92


1340
GLU
OE2
17.717
21.235
23.997
32.19


1341
ASN
N
21.623
18.021
22.954
34.04


1342
ASN
CA
21.013
16.727
22.728
35.49


1343
ASN
C
19.536
17.002
22.721
35.58


1344
ASN
O
18.959
17.366
23.723
36.35


1345
ASN
CB
21.368
15.757
23.883
44.05


1346
ASN
CG
20.671
14.415
23.812
52.92


1347
ASN
OD1
19.515
14.311
23.355
44.48


1348
ASN
ND2
21.363
13.396
24.335
42.29


1349
LEU
N
18.930
16.882
21.595
29.96


1350
LEU
CA
17.542
17.220
21.535
30.39


1351
LEU
C
16.669
16.255
22.278
44.87


1352
LEU
O
15.455
16.484
22.392
46.33


1353
LEU
CB
17.041
17.273
20.108
28.60


1354
LEU
CG
17.610
18.466
19.424
34.04


1355
LEU
CD1
17.221
18.478
17.959
34.74


1356
LEU
CD2
17.091
19.717
20.120
39.55


1357
THR
N
17.269
15.169
22.738
43.23


1358
THR
CA
16.475
14.185
23.405
45.55


1359
THR
C
16.335
14.567
24.850
50.45


1360
THR
O
15.215
14.792
25.347
50.59


1361
THR
CB
17.157
12.816
23.285
71.99


1362
THR
OG1
17.334
12.446
21.931
84.31


1363
THR
CG2
16.334
11.768
24.000
76.78


1364
THR
N
17.522
14.663
25.474
44.41


1365
THR
CA
17.631
14.986
26.856
42.87


1366
THR
C
17.421
16.444
27.075
48.48


1367
THR
O
16.952
16.882
28.107
52.02


1368
THR
CB
18.984
14.575
27.417
55.05


1369
THR
OG1
20.046
15.266
26.798
63.24


1370
THR
CG2
19.150
13.086
27.255
59.51


1371
GLN
N
17.784
17.191
26.081
41.45


1372
GLN
CA
17.729
18.616
26.132
38.83


1373
GLN
C
18.894
19.129
26.948
39.20


1374
GLN
O
18.978
20.280
27.345
40.16


1375
GLN
CB
16.416
19.191
26.628
41.08


1376
GLN
CG
15.319
19.228
25.576
61.17


1377
GLN
CD
14.099
19.968
26.091
89.86


1378
GLN
OE1
13.915
20.136
27.317
69.61


1379
GLN
NE2
13.273
20.437
25.155
100.00


1380
GLU
N
19.813
18.252
27.212
35.40


1381
GLU
CA
21.012
18.645
27.881
35.65


1382
GLU
C
21.902
19.442
26.872
35.40


1383
GLU
O
21.846
19.311
25.623
30.83


1384
GLU
CB
21.695
17.380
28.399
38.29


1385
GLU
CG
23.069
17.598
29.043
53.86


1386
GLU
CD
23.653
16.237
29.306
86.06


1387
GLU
OE1
22.927
15.190
29.234
47.15


1388
GLU
OE2
24.973
16.313
29.499
61.60


1389
THR
N
22.711
20.331
27.382
30.84


1390
THR
CA
23.466
21.110
26.458
30.66


1391
THR
C
24.932
21.176
26.816
36.12


1392
THR
O
25.281
21.143
28.021
33.20


1393
THR
CB
22.790
22.467
26.411
39.57


1394
THR
OG1
22.486
22.795
25.083
53.77


1395
THR
CG2
23.565
23.531
27.180
23.13


1396
ARG
N
25.775
21.267
25.751
30.39


1397
ARG
CA
27.226
21.319
25.923
29.24


1398
ARG
C
27.878
22.407
25.096
25.15


1399
ARG
O
27.469
22.689
23.981
24.36


1400
ARG
CB
27.876
19.985
25.554
35.10


1401
ARG
CG
27.814
18.914
26.635
47.54


1402
ARG
CD
28.971
17.902
26.645
35.93


1403
ARG
NE
28.439
16.717
27.258
45.02


1404
ARG
CZ
28.503
15.548
26.702
70.35


1405
ARG
NH1
29.148
15.393
25.541
42.87


1406
ARG
NH2
27.922
14.522
27.339
59.02


1407
GLU
N
28.876
23.022
25.717
22.49


1408
GLU
CA
29.661
24.057
25.109
21.66


1409
GLU
C
30.904
23.440
24.481
24.49


1410
GLU
O
31.646
22.763
25.168
21.92


1411
GLU
CB
30.223
25.020
26.131
23.64


1412
GLU
CG
31.072
26.050
25.395
37.97


1413
GLU
CD
31.821
26.929
26.332
70.67


1414
GLU
OE1
31.279
27.585
27.207
100.00


1415
GLU
OE2
33.108
26.854
26.147
87.35


1416
ILE
N
31.145
23.707
23.201
20.06


1417
ILE
CA
32.319
23.179
22.541
19.28


1418
ILE
C
33.071
24.345
21.942
22.12


1419
ILE
O
32.454
25.302
21.437
21.81


1420
ILE
CB
31.898
22.286
21.385
22.39


1421
ILE
CG1
30.838
21.236
21.764
21.96


1422
ILE
CG2
33.122
21.719
20.656
20.30


1423
ILE
CD1
31.341
20.178
22.720
24.63


1424
LEU
N
34.376
24.265
21.944
16.47


1425
LEU
CA
35.137
25.326
21.321
16.94


1426
LEU
C
35.661
24.796
20.041
21.55


1427
LEU
O
36.126
23.648
19.980
20.21


1428
LEU
CB
36.341
25.704
22.198
18.75


1429
LEU
CG
35.902
26.118
23.634
26.04


1430
LEU
CD1
37.112
26.450
24.540
27.16


1431
LEU
CD2
35.041
27.336
23.494
24.28


1432
HIS
N
35.635
25.621
19.021
16.36


1433
HIS
CA
36.118
25.183
17.703
14.50


1434
HIS
C
37.275
26.073
17.333
20.44


1435
HIS
O
37.118
27.293
17.360
20.81


1436
HIS
CB
34.956
25.388
16.717
15.22


1437
HIS
CG
35.150
24.834
15.350
17.70


1438
HIS
ND1
35.394
25.650
14.280
18.12


1439
HIS
CD2
35.045
23.553
14.893
18.74


1440
HIS
CE1
35.513
24.853
13.225
17.96


1441
HIS
NE2
35.316
23.575
13.552
17.01


1442
PHE
N
38.456
25.476
17.039
14.68


1443
PHE
CA
39.642
26.223
16.705
14.36


1444
PHE
C
39.905
25.964
15.252
18.76


1445
PHE
O
40.224
24.844
14.924
19.29


1446
PHE
CB
40.854
25.765
17.540
14.14


1447
PHE
CG
40.543
25.886
19.001
15.56


1448
PHE
CD1
40.812
27.078
19.679
19.52


1449
PHE
CD2
39.966
24.812
19.687
19.04


1450
PHE
CE1
40.493
27.165
21.038
21.39


1451
PHE
CE2
39.691
24.853
21.057
21.60


1452
PHE
CZ
39.956
26.053
21.711
19.12


1453
HIS
N
39.729
26.988
14.398
16.34


1454
HIS
CA
39.850
26.842
12.954
16.68


1455
HIS
C
41.036
27.540
12.393
22.59


1456
HIS
O
41.056
28.776
12.342
20.03


1457
HIS
CB
38.597
27.462
12.336
18.43


1458
HIS
CG
38.504
27.092
10.899
22.05


1459
HIS
ND1
37.487
27.555
10.113
21.32


1460
HIS
CD2
39.322
26.311
10.139
23.08


1461
HIS
CE1
37.665
27.073
8.892
20.85


1462
HIS
NE2
38.738
26.297
8.857
22.16


1463
TYR
N
42.029
26.753
11.977
17.95


1464
TYR
CA
43.277
27.301
11.440
17.43


1465
TYR
C
43.022
27.495
9.978
23.32


1466
TYR
O
42.787
26.542
9.283
19.33


1467
TYR
CB
44.414
26.250
11.602
16.22


1468
TYR
CG
45.848
26.801
11.601
19.15


1469
TYR
CD1
46.322
27.564
10.527
21.35


1470
TYR
CD2
46.732
26.525
12.639
19.74


1471
TYR
CE1
47.633
28.058
10.473
20.97


1472
TYR
CE2
48.053
26.987
12.600
20.96


1473
TYR
CZ
48.500
27.758
11.521
24.03


1474
TYR
OH
49.771
28.237
11.483
27.87


1475
THR
N
43.075
28.699
9.495
19.92


1476
THR
CA
42.722
28.877
8.099
22.16


1477
THR
C
43.882
29.154
7.134
28.45


1478
THR
O
43.647
29.392
5.946
29.06


1479
THR
CB
41.656
30.007
8.008
25.85


1480
THR
OG1
42.260
31.210
8.473
23.68


1481
THR
CG2
40.470
29.686
8.925
20.99


1482
THR
N
45.126
29.138
7.580
21.17


1483
THR
CA
46.174
29.416
6.619
20.89


1484
THR
C
47.190
28.284
6.556
28.24


1485
THR
O
48.385
28.506
6.365
28.74


1486
THR
CB
46.906
30.686
7.023
27.18


1487
THR
OG1
47.257
30.490
8.372
25.28


1488
THR
CG2
46.033
31.944
6.834
22.60


1489
TRP
N
46.743
27.029
6.778
21.40


1490
TRP
CA
47.670
25.898
6.710
18.45


1491
TRP
C
47.214
25.059
5.472
23.97


1492
TRP
O
46.155
24.444
5.460
19.44


1493
TRP
CB
47.520
25.065
7.977
15.94


1494
TRP
CG
48.522
23.957
8.065
15.20


1495
TRP
CD1
49.281
23.420
7.059
17.12


1496
TRP
CD2
48.839
23.238
9.266
15.16


1497
TRP
NE1
50.080
22.423
7.592
16.60


1498
TRP
CE2
49.810
22.295
8.937
19.35


1499
TRP
CE3
48.376
23.353
10.604
16.48


1500
TRP
CZ2
50.290
21.421
9.907
20.83


1501
TRP
CZ3
48.843
22.520
11.569
17.13


1502
TRP
CH2
49.763
21.536
11.205
19.65


1503
PRO
N
47.948
25.153
4.377
20.91


1504
PRO
CA
47.535
24.503
3.150
19.93


1505
PRO
C
47.609
22.996
3.191
21.72


1506
PRO
O
48.534
22.409
3.802
19.55


1507
PRO
CB
48.501
24.984
2.021
23.28


1508
PRO
CG
49.570
25.796
2.717
28.22


1509
PRO
CD
49.234
25.901
4.224
21.68


1510
ASP
N
46.667
22.415
2.435
20.26


1511
ASP
CA
46.638
20.993
2.325
17.54


1512
ASP
C
48.007
20.561
1.755
23.68


1513
ASP
O
48.601
21.308
0.939
21.00


1514
ASP
CB
45.449
20.625
1.461
15.69


1515
ASP
CG
45.196
19.140
1.667
19.13


1516
ASP
OD1
45.886
18.423
2.440
20.93


1517
ASP
OD2
44.249
18.644
0.903
18.68


1518
PHE
N
48.544
19.411
2.224
16.97


1519
PHE
CA
49.870
18.965
1.826
20.13


1520
PHE
C
50.957
19.945
2.133
25.12


1521
PHE
O
52.103
19.742
1.643
22.55


1522
PHE
CB
49.924
18.631
0.326
26.08


1523
PHE
CG
49.104
17.401
0.246
35.80


1524
PHE
CD1
49.297
16.474
1.282
48.33


1525
PHE
CD2
48.084
17.211
−0.681
40.42


1526
PHE
CE1
48.566
15.292
1.405
48.19


1527
PHE
CE2
47.393
15.996
−0.632
45.67


1528
PHE
CZ
47.618
15.075
0.407
46.93


1529
GLY
N
50.632
21.004
2.915
20.53


1530
GLY
CA
51.683
21.971
3.227
19.53


1531
GLY
C
52.004
22.104
4.708
21.83


1532
GLY
O
51.696
21.221
5.531
18.25


1533
VAL
N
52.661
23.217
5.033
18.02


1534
VAL
CA
53.016
23.487
6.390
16.83


1535
VAL
C
52.534
24.857
6.791
24.11


1536
VAL
O
52.177
25.662
5.955
24.27


1537
VAL
CB
54.512
23.437
6.545
20.78


1538
VAL
CG1
54.973
22.026
6.244
19.08


1539
VAL
CG2
55.079
24.462
5.559
22.82


1540
PRO
N
52.473
25.117
8.096
21.39


1541
PRO
CA
52.081
26.441
8.616
20.99


1542
PRO
C
53.080
27.518
8.157
26.47


1543
PRO
O
54.203
27.218
7.754
25.08


1544
PRO
CB
52.116
26.310
10.170
21.11


1545
PRO
CG
52.245
24.819
10.510
21.50


1546
PRO
CD
52.674
24.115
9.211
19.66


1547
GLU
N
52.696
28.777
8.213
24.24


1548
GLU
CA
53.593
29.831
7.749
23.61


1549
GLU
C
54.886
29.923
8.532
28.04


1550
GLU
O
55.907
30.309
7.997
26.16


1551
GLU
CB
52.881
31.191
7.690
25.09


1552
GLU
CG
51.548
31.090
6.895
64.56


1553
GLU
CD
50.479
32.181
7.111
100.00


1554
GLU
OE1
49.716
32.227
8.113
79.43


1555
GLU
OE2
50.381
33.007
6.070
91.77


1556
SER
N
54.859
29.633
9.821
22.79


1557
SER
CA
56.080
29.729
10.605
20.38


1558
SER
C
55.893
28.889
11.822
23.57


1559
SER
O
54.788
28.588
12.204
24.21


1560
SER
CB
56.352
31.159
11.079
23.98


1561
SER
OG
55.221
31.636
11.819
21.35


1562
PRO
N
56.970
28.495
12.436
22.91


1563
PRO
CA
56.805
27.775
13.649
23.08


1564
PRO
C
56.050
28.657
14.655
26.93


1565
PRO
O
55.238
28.194
15.396
25.45


1566
PRO
CB
58.230
27.505
14.170
24.65


1567
PRO
CG
59.143
27.550
12.965
28.02


1568
PRO
CD
58.397
28.442
11.979
23.89


1569
ALA
N
56.300
29.973
14.661
23.54


1570
ALA
CA
55.629
30.881
15.613
21.90


1571
ALA
C
54.118
30.891
15.479
20.92


1572
ALA
O
53.348
30.851
16.457
19.69


1573
ALA
CB
56.248
32.309
15.569
21.00


1574
SER
N
53.675
30.917
14.234
20.18


1575
SER
CA
52.201
30.957
14.031
21.57


1576
SER
C
51.539
29.677
14.476
24.10


1577
SER
O
50.457
29.670
15.047
23.15


1578
SER
CB
51.769
31.348
12.606
25.87


1579
SER
OG
52.780
31.001
11.688
40.00


1580
PHE
N
52.229
28.573
14.201
19.09


1581
PHE
CA
51.685
27.283
14.553
15.85


1582
PHE
C
51.650
27.200
16.075
21.97


1583
PHE
O
50.659
26.814
16.684
20.90


1584
PHE
CB
52.611
26.166
13.984
18.25


1585
PHE
CG
52.293
24.814
14.607
18.09


1586
PHE
CD1
51.234
24.063
14.104
16.30


1587
PHE
CD2
53.032
24.327
15.687
19.26


1588
PHE
CE1
50.907
22.860
14.722
18.09


1589
PHE
CE2
52.685
23.149
16.344
23.27


1590
PHE
CZ
51.600
22.423
15.850
21.69


1591
LEU
N
52.774
27.544
16.720
20.33


1592
LEU
CA
52.866
27.418
18.177
19.90


1593
LEU
C
51.888
28.318
18.868
23.96


1594
LEU
O
51.233
27.949
19.866
23.17


1595
LEU
CB
54.290
27.689
18.661
20.12


1596
LEU
CG
55.212
26.537
18.324
22.21


1597
LEU
CD1
56.679
26.965
18.499
22.08


1598
LEU
CD2
54.843
25.331
19.215
23.19


1599
ASN
N
51.778
29.520
18.303
22.18


1600
ASN
CA
50.801
30.490
18.835
21.35


1601
ASN
C
49.403
29.847
18.865
21.98


1602
ASN
O
48.693
29.928
19.870
21.88


1603
ASN
CB
50.785
31.816
18.027
20.82


1604
ASN
CG
49.807
32.839
18.619
24.28


1605
ASN
OD1
49.974
33.256
19.783
21.90


1606
ASN
ND2
48.763
33.220
17.844
19.52


1607
PHE
N
49.044
29.156
17.743
18.21


1608
PHE
CA
47.745
28.501
17.628
14.93


1609
PHE
C
47.666
27.300
18.571
19.31


1610
PHE
O
46.638
27.092
19.233
19.07


1611
PHE
CB
47.530
28.099
16.167
15.26


1612
PHE
CG
46.276
27.312
15.946
19.10


1613
PHE
CD1
45.072
27.942
15.602
22.25


1614
PHE
CD2
46.280
25.910
16.038
14.28


1615
PHE
CE1
43.887
27.210
15.433
20.75


1616
PHE
CE2
45.122
25.167
15.823
12.24


1617
PHE
CZ
43.919
25.815
15.533
13.08


1618
LEU
N
48.750
26.511
18.662
18.17


1619
LEU
CA
48.729
25.368
19.546
17.98


1620
LEU
C
48.499
25.780
21.000
21.46


1621
LEU
O
47.707
25.217
21.756
18.26


1622
LEU
CB
50.052
24.635
19.403
18.33


1623
LEU
CG
50.151
23.515
20.450
21.15


1624
LEU
CD1
51.503
22.791
20.311
23.59


1625
LEU
CD2
48.978
22.520
20.369
15.46


1626
PHE
N
49.225
26.808
21.416
20.08


1627
PHE
CA
49.049
27.353
22.789
21.32


1628
PHE
C
47.628
27.968
23.006
24.42


1629
PHE
O
47.052
27.870
24.091
24.60


1630
PHE
CB
50.175
28.286
23.244
20.93


1631
PHE
CG
51.389
27.451
23.568
25.75


1632
PHE
CD1
51.876
26.502
22.666
24.29


1633
PHE
CD2
52.059
27.590
24.788
33.03


1634
PHE
CE1
52.958
25.669
22.967
25.19


1635
PHE
CE2
53.152
26.773
25.100
36.27


1636
PHE
CZ
53.595
25.799
24.198
30.54


1637
LYS
N
47.012
28.564
21.981
19.37


1638
LYS
CA
45.650
29.029
22.169
19.01


1639
LYS
C
44.755
27.830
22.565
23.16


1640
LYS
O
43.965
27.875
23.510
20.57


1641
LYS
CB
45.064
29.654
20.900
20.68


1642
LYS
CG
44.966
31.167
21.019
54.23


1643
LYS
CD
43.679
31.660
21.671
58.81


1644
LYS
CE
43.329
33.110
21.340
79.60


1645
LYS
NZ
42.204
33.258
20.403
90.92


1646
VAL
N
44.903
26.725
21.833
18.90


1647
VAL
CA
44.143
25.527
22.117
17.53


1648
VAL
C
44.447
25.027
23.508
21.15


1649
VAL
O
43.558
24.712
24.284
19.52


1650
VAL
CB
44.432
24.450
21.047
17.34


1651
VAL
CG1
43.692
23.154
21.348
16.63


1652
VAL
CG2
44.052
24.997
19.628
15.16


1653
ARG
N
45.712
24.939
23.832
20.55


1654
ARG
CA
46.047
24.444
25.161
19.47


1655
ARG
C
45.455
25.327
26.259
21.39


1656
ARG
O
44.954
24.911
27.288
21.16


1657
ARG
CB
47.560
24.512
25.353
17.77


1658
ARG
CG
48.312
23.372
24.672
24.26


1659
ARG
CD
49.824
23.590
24.620
22.42


1660
ARG
NE
50.439
22.292
24.419
26.10


1661
ARG
CZ
51.464
21.787
25.113
40.08


1662
ARG
NH1
52.063
22.472
26.095
23.77


1663
ARG
NH2
51.909
20.558
24.796
21.91


1664
GLU
N
45.604
26.581
26.047
20.31


1665
GLU
CA
45.141
27.497
27.028
21.25


1666
GLU
C
43.668
27.493
27.214
26.86


1667
GLU
O
43.228
27.801
28.314
30.19


1668
GLU
CB
45.646
28.874
26.753
23.38


1669
GLU
CG
47.087
28.893
27.173
37.92


1670
GLU
CD
47.736
30.184
26.883
65.18


1671
GLU
OE1
47.282
30.979
26.063
63.04


1672
GLU
OE2
48.853
30.321
27.578
59.99


1673
SER
N
42.897
27.123
26.213
20.78


1674
SER
CA
41.438
27.087
26.408
20.46


1675
SER
C
41.009
26.041
27.387
30.52


1676
SER
O
39.864
25.951
27.744
37.57


1677
SER
CB
40.714
26.707
25.130
17.75


1678
SER
OG
40.998
25.358
24.799
21.13


1679
GLY
N
41.850
25.128
27.755
27.53


1680
GLY
CA
41.324
24.128
28.636
24.97


1681
GLY
C
40.817
22.896
27.894
35.66


1682
GLY
O
40.571
21.813
28.504
38.98


1683
SER
N
40.733
23.002
26.556
26.31


1684
SER
CA
40.241
21.873
25.787
23.11


1685
SER
C
41.002
20.591
25.925
33.29


1686
SER
O
40.402
19.563
25.614
33.64


1687
SER
CB
40.151
22.177
24.303
24.92


1688
SER
OG
39.263
23.274
24.065
24.93


1689
LEU
N
42.318
20.630
26.294
30.38


1690
LEU
CA
43.103
19.378
26.359
30.40


1691
LEU
C
43.108
18.701
27.742
38.35


1692
LEU
O
43.678
17.631
27.992
38.03


1693
LEU
CB
44.513
19.515
25.757
29.26


1694
LEU
CG
44.530
20.316
24.461
31.07


1695
LEU
CD1
45.948
20.591
24.014
27.31


1696
LEU
CD2
43.820
19.572
23.354
34.10


1697
SER
N
42.463
19.367
28.644
34.73


1698
SER
CA
42.363
18.870
29.968
34.22


1699
SER
C
41.847
17.426
30.022
36.01


1700
SER
O
40.925
17.051
29.369
31.19


1701
SER
CB
41.501
19.801
30.780
39.43


1702
SER
OG
41.658
19.437
32.131
55.74


1703
PRO
N
42.456
16.621
30.848
39.48


1704
PRO
CA
42.093
15.228
31.048
39.86


1705
PRO
C
40.73O
15.105
31.735
38.86


1706
PRO
O
40.123
14.050
31.847
37.15


1707
PRO
CB
43.162
14.696
31.998
42.88


1708
PRO
CG
43.756
15.909
32.728
48.04


1709
PRO
CD
43.253
17.145
31.996
43.33


1710
GLU
N
40.212
16.194
32.214
32.75


1711
GLU
CA
38.901
16.068
32.791
33.48


1712
GLU
C
37.828
16.086
31.693
31.63


1713
GLU
O
36.656
16.014
31.931
31.89


1714
GLU
CB
38.647
17.159
33.840
37.32


1715
GLU
CG
38.309
18.559
33.240
65.45


1716
GLU
CD
39.318
19.626
33.589
92.79


1717
GLU
OE1
40.366
19.358
34.151
100.00


1718
GLU
OE2
39.027
20.832
33.145
79.45


1719
HIS
N
38.217
16.238
30.459
23.47


1720
HIS
CA
37.246
16.264
29.407
21.41


1721
HIS
C
37.579
15.102
28.544
24.76


1722
HIS
O
38.664
14.584
28.727
24.90


1723
HIS
CB
37.581
17.439
28.476
23.84


1724
HIS
CG
37.356
18.755
29.102
29.53


1725
HIS
ND1
36.121
19.085
29.633
32.52


1726
HIS
CD2
38.191
19.824
29.252
34.49


1727
HIS
CE1
36.203
20.348
30.081
33.65


1728
HIS
NE2
37.441
20.813
29.875
35.22


1729
GLY
N
36.738
14.774
27.539
20.61


1730
GLY
CA
37.086
13.704
26.621
18.66


1731
GLY
C
38.225
14.238
25.771
24.63


1732
GLY
O
38.659
15.427
25.902
26.39


1733
PRO
N
38.720
13.391
24.886
20.23


1734
PRO
CA
39.824
13.749
23.973
16.08


1735
PRO
C
39.406
14.853
23.015
16.63


1736
PRO
O
38.315
14.885
22.519
21.70


1737
PRO
CB
40.065
12.516
23.099
18.85


1738
PRO
CG
39.214
11.419
23.667
23.51


1739
PRO
CD
38.245
12.018
24.690
21.40


1740
VAL
N
40.277
15.758
22.729
17.27


1741
VAL
CA
39.952
16.799
21.788
16.61


1742
VAL
C
39.821
16.100
20.459
20.32


1743
VAL
O
40.473
15.057
20.168
20.45


1744
VAL
CB
41.125
17.820
21.737
20.35


1745
VAL
CG1
42.315
17.135
21.117
22.42


1746
VAL
CG2
40.889
19.002
20.793
20.42


1747
VAL
N
38.972
16.637
19.619
16.18


1748
VAL
CA
38.847
16.060
18.263
13.46


1749
VAL
C
39.700
16.901
17.328
20.85


1750
VAL
O
39.635
18.187
17.316
22.85


1751
VAL
CB
37.396
16.152
17.783
16.77


1752
VAL
CG1
37.337
15.760
16.317
16.82


1753
VAL
CG2
36.566
15.164
18.549
16.12


1754
VAL
N
40.549
16.250
16.565
16.13


1755
VAL
CA
41.389
17.029
15.642
14.73


1756
VAL
C
41.154
16.603
14.236
19.68


1757
VAL
O
41.111
15.408
13.968
18.53


1758
VAL
CB
42.844
16.737
15.897
16.28


1759
VAL
CG1
43.703
17.511
14.901
17.56


1760
VAL
CG2
43.184
17.097
17.349
17.81


1761
HIS
N
40.996
17.532
13.289
15.11


1762
HIS
CA
40.798
17.040
11.911
12.07


1763
HIS
C
41.283
18.025
10.893
18.30


1764
HIS
O
41.478
19.204
11.185
18.91


1765
HIS
CB
39.337
16.682
11.545
13.93


1766
HIS
CG
38.478
17.919
11.267
15.77


1767
HIS
ND1
38.367
18.469
9.979
15.86


1768
HIS
CD2
37.681
18.652
12.088
16.69


1769
HIS
CE1
37.560
19.518
10.045
16.85


1770
HIS
NE2
37.137
19.670
11.291
18.34


1771
CYS
N
41.470
17.478
9.681
16.12


1772
CYS
CA
41.899
18.201
8.547
13.36


1773
CYS
C
40.993
17.660
7.461
17.96


1774
CYS
O
39.874
17.322
7.714
14.94


1775
CYS
CB
43.356
18.020
8.128
12.46


1776
CYS
SG
44.095
16.346
8.360
18.95


1777
SER
N
41.479
17.548
6.218
15.33


1778
SER
CA
40.606
16.949
5.208
15.04


1779
SER
C
40.523
15.407
5.439
18.57


1780
SER
O
39.439
14.799
5.469
17.07


1781
SER
CB
41.042
17.237
3.766
14.15


1782
SER
OG
40.022
16.672
2.921
17.05


1783
ALA
N
41.695
14.781
5.624
14.98


1784
ALA
CA
41.676
13.317
5.798
13.26


1785
ALA
C
41.900
12.903
7.242
18.49


1786
ALA
O
41.702
11.727
7.613
17.47


1787
ALA
CB
42.793
12.703
4.988
14.41


1788
GLY
N
42.343
13.867
8.075
16.70


1789
GLY
CA
42.600
13.538
9.471
15.45


1790
GLY
C
43.930
12.809
9.660
18.39


1791
GLY
O
44.071
11.993
10.600
16.53


1792
ILE
N
44.929
13.082
8.789
13.74


1793
ILE
CA
46.226
12.446
8.919
11.49


1794
ILE
C
47.402
13.347
8.720
18.18


1795
ILE
O
48.386
13.343
9.475
19.37


1796
ILE
CB
46.405
11.141
8.141
16.27


1797
ILE
CG1
46.367
11.366
6.605
17.55


1798
ILE
CG2
45.308
10.153
8.566
15.49


1799
ILE
CD1
46.493
10.057
5.781
14.58


1800
GLY
N
47.379
14.148
7.683
16.11


1801
GLY
CA
48.606
14.939
7.449
16.70


1802
GLY
C
48.766
16.139
8.371
19.48


1803
GLY
O
49.669
16.167
9.200
20.37


1804
ARG
N
47.898
17.159
8.203
14.27


1805
ARG
CA
47.981
18.302
9.086
14.68


1806
ARG
C
47.634
17.835
10.502
17.73


1807
ARG
O
48.295
18.218
11.470
19.43


1808
ARG
CB
47.114
19.444
8.599
12.68


1809
ARG
CG
47.672
20.033
7.287
13.57


1810
ARG
CD
46.645
20.986
6.671
11.34


1811
ARG
NE
45.594
20.244
5.930
16.97


1812
ARG
CZ
44.676
20.854
5.129
31.69


1813
ARG
NH1
44.618
22.185
4.971
16.84


1814
ARG
NH2
43.766
20.109
4.490
15.94


1815
SER
N
46.626
16.986
10.647
15.68


1816
SER
CA
46.298
16.517
12.015
14.86


1817
SER
C
47.460
15.831
12.671
17.12


1818
SER
O
47.726
16.037
13.863
16.53


1819
SER
CB
45.169
15.510
11.989
17.35


1820
SER
OG
44.028
16.136
11.424
17.53


1821
GLY
N
48.157
14.979
11.913
15.45


1822
GLY
CA
49.301
14.268
12.486
11.73


1823
GLY
C
50.394
15.213
12.935
17.63


1824
GLY
O
51.056
15.041
13.964
17.72


1825
THR
N
50.627
16.231
12.100
16.30


1826
THR
CA
51.651
17.225
12.377
15.64


1827
THR
C
51.360
17.997
13.664
19.70


1828
THR
O
52.171
18.184
14.543
17.95


1829
THR
CB
51.794
18.168
11.171
23.66


1830
THR
OG1
52.110
17.428
9.987
19.58


1831
THR
CG2
52.870
19.217
11.433
19.33


1832
PHE
N
50.158
18.420
13.807
15.63


1833
PHE
CA
49.780
19.140
14.983
15.63


1834
PHE
C
49.909
18.259
16.248
20.88


1835
PHE
O
50.425
18.670
17.305
20.45


1836
PHE
CB
48.260
19.563
14.772
17.22


1837
PHE
CG
47.593
20.201
15.997
17.55


1838
PHE
CD1
47.575
21.585
16.155
17.33


1839
PHE
CD2
46.967
19.435
16.983
17.40


1840
PHE
CE1
46.983
22.172
17.278
17.10


1841
PHE
CE2
46.361
20.001
18.114
18.42


1842
PHE
CZ
46.365
21.392
18.257
14.40


1843
CYS
N
49.390
17.033
16.193
17.18


1844
CYS
CA
49.432
16.201
17.366
14.77


1845
CYS
C
50.843
15.806
17.694
21.33


1846
CYS
O
51.225
15.694
18.842
20.61


1847
CYS
CB
48.573
14.933
17.191
18.22


1848
CYS
SG
46.804
15.307
17.081
23.37


1849
LEU
N
51.643
15.520
16.693
19.44


1850
LEU
CA
52.998
15.101
17.015
18.15


1851
LEU
C
53.714
16.200
17.797
19.49


1852
LEU
O
54.425
15.954
18.786
19.58


1853
LEU
CB
53.792
14.823
15.705
16.40


1854
LEU
CG
55.288
14.537
15.965
18.63


1855
LEU
CD1
55.482
13.249
16.751
16.35


1856
LEU
CD2
55.942
14.240
14.617
19.47


1857
ALA
N
53.571
17.449
17.313
16.69


1858
ALA
CA
54.249
18.534
18.012
15.40


1859
ALA
C
53.697
18.630
19.431
19.18


1860
ALA
O
54.419
18.775
20.406
16.89


1861
ALA
CB
54.115
19.859
17.273
14.90


1862
ASP
N
52.390
18.527
19.557
19.72


1863
ASP
CA
51.781
18.658
20.893
17.54


1864
ASP
C
52.338
17.650
21.887
20.70


1865
ASP
O
52.697
17.949
23.038
19.79


1866
ASP
CB
50.237
18.552
20.829
15.42


1867
ASP
CG
49.674
18.953
22.159
24.54


1868
ASP
OD1
50.072
19.914
22.820
19.87


1869
ASP
OD2
48.833
18.076
22.624
22.29


1870
THR
N
52.385
16.427
21.396
16.78


1871
THR
CA
52.782
15.309
22.210
14.97


1872
THR
C
54.217
15.416
22.614
18.91


1873
THR
O
54.563
15.159
23.809
16.57


1874
THR
CB
52.438
13.929
21.591
19.52


1875
THR
OG1
51.035
13.752
21.566
22.01


1876
THR
CG2
53.027
12.780
22.446
15.17


1877
CYS
N
55.074
15.710
21.605
16.93


1878
CYS
CA
56.498
15.818
21.947
16.87


1879
CYS
C
56.751
16.927
22.968
20.74


1880
CYS
O
57.647
16.825
23.812
19.23


1881
CYS
CB
57.335
16.123
20.706
18.21


1882
CYS
SG
57.376
14.721
19.578
21.43


1883
LEU
N
55.983
17.999
22.886
17.24


1884
LEU
CA
56.208
19.110
23.805
16.36


1885
LEU
C
55.758
18.707
25.185
22.13


1886
LEU
O
56.343
19.082
26.201
21.35


1887
LEU
CB
55.501
20.411
23.335
15.49


1888
LEU
CG
56.258
21.020
22.155
16.90


1889
LEU
CD1
55.474
22.152
21.560
18.67


1890
LEU
CD2
57.642
21.489
22.581
19.42


1891
LEU
N
54.709
17.914
25.244
18.58


1892
LEU
CA
54.187
17.454
26.563
19.33


1893
LEU
C
55.127
16.424
27.211
20.57


1894
LEU
O
55.403
16.398
28.406
17.16


1895
LEU
CB
52.758
16.888
26.411
20.29


1896
LEU
CG
52.083
16.494
27.720
23.78


1897
LEU
CD1
51.799
17.757
28.557
22.08


1898
LEU
CD2
50.756
15.824
27.386
26.13


1899
LEU
N
55.661
15.528
26.417
20.05


1900
LEU
CA
56.607
14.567
27.014
22.38


1901
LEU
C
57.798
15.295
27.539
21.44


1902
LEU
O
58.333
14.922
28.548
18.07


1903
LEU
CB
57.204
13.588
25.971
23.67


1904
LEU
CG
56.223
12.489
25.668
30.34


1905
LEU
CD1
56.535
11.952
24.272
35.67


1906
LEU
CD2
56.358
11.418
26.732
23.09


1907
MET
N
58.247
16.315
26.802
17.46


1908
MET
CA
59.411
17.026
27.246
21.88


1909
MET
C
59.093
17.791
28.540
23.63


1910
MET
O
59.925
17.939
29.443
21.17


1911
MET
CB
60.016
17.837
26.046
26.35


1912
MET
CG
60.123
19.321
26.201
31.09


1913
MET
SD
61.319
20.100
25.086
31.12


1914
MET
CE
61.218
18.941
23.667
24.10


1915
ASP
N
57.837
18.250
28.614
21.37


1916
ASP
CA
57.357
18.992
29.777
19.58


1917
ASP
C
57.355
18.111
31.012
26.30


1918
ASP
O
57.669
18.490
32.147
25.46


1919
ASP
CB
55.936
19.493
29.486
18.02


1920
ASP
CG
55.662
20.778
30.190
23.00


1921
ASP
OD1
56.518
21.337
30.864
26.14


1922
ASP
OD2
54.428
21.203
30.067
21.46


1923
LYS
N
56.941
16.910
30.809
26.75


1924
LYS
CA
56.835
15.971
31.911
27.98


1925
LYS
C
58.142
15.701
32.588
30.57


1926
LYS
O
58.233
15.653
33.824
29.41


1927
LYS
CB
56.113
14.673
31.511
31.11


1928
LYS
CG
56.050
13.703
32.679
62.81


1929
LYS
CD
54.796
12.831
32.771
87.49


1930
LYS
CE
54.830
11.905
34.006
100.00


1931
LYS
NZ
54.107
10.613
33.862
100.00


1932
ARG
N
59.175
15.573
31.790
29.07


1933
ARG
CA
60.454
15.266
32.352
31.74


1934
ARG
C
61.458
16.356
32.286
38.39


1935
ARG
O
62.576
16.155
32.699
42.73


1936
ARG
CB
61.007
14.104
31.574
42.79


1937
ARG
CG
60.626
14.244
30.128
44.98


1938
ARG
CD
61.065
13.064
29.267
65.93


1939
ARG
NE
60.195
11.933
29.445
74.57


1940
ARG
CZ
59.885
10.983
28.560
88.88


1941
ARG
NH1
60.356
10.889
27.280
42.03


1942
ARG
NH2
59.037
10.075
29.022
91.14


1943
LYS
N
61.090
17.490
31.753
28.22


1944
LYS
CA
62.065
18.538
31.662
25.40


1945
LYS
C
63.354
18.059
31.041
28.13


1946
LYS
O
64.435
18.477
31.438
25.94


1947
LYS
CB
62.253
19.262
32.958
26.58


1948
LYS
CG
60.936
19.905
33.457
27.81


1949
LYS
CD
60.409
21.051
32.575
14.64


1950
LYS
CE
59.256
21.768
33.219
19.71


1951
LYS
NZ
58.583
22.690
32.312
24.14


1952
ASP
N
63.240
17.207
30.024
22.76


1953
ASP
CA
64.428
16.721
29.406
22.09


1954
ASP
C
64.228
16.564
27.898
30.50


1955
ASP
O
63.820
15.533
27.405
33.52


1956
ASP
CB
64.769
15.377
30.068
24.25


1957
ASP
CG
65.984
14.741
29.416
34.47


1958
ASP
OD1
66.675
15.328
28.608
33.87


1959
ASP
OD2
66.182
13.489
29.778
42.04


1960
PRO
N
64.523
17.584
27.151
24.81


1961
PRO
CA
64.355
17.595
25.725
25.70


1962
PRO
C
65.131
16.551
24.997
31.12


1963
PRO
O
64.707
16.018
23.971
31.92


1964
PRO
CB
64.832
18.944
25.251
29.74


1965
PRO
CG
64.947
19.803
26.511
32.73


1966
PRO
CD
65.066
18.845
27.678
26.52


1967
SER
N
66.264
16.244
25.538
29.07


1968
SER
CA
67.077
15.273
24.890
31.78


1969
SER
C
66.479
13.911
24.933
37.92


1970
SER
O
66.793
13.023
24.150
45.55


1971
SER
CB
68.530
15.309
25.381
42.27


1972
SER
OG
69.183
16.449
24.808
59.55


1973
SER
N
65.580
13.735
25.830
28.18


1974
SER
CA
64.970
12.446
25.947
28.28


1975
SER
C
63.888
12.202
24.886
32.74


1976
SER
O
63.293
11.107
24.796
34.35


1977
SER
CB
64.304
12.317
27.328
30.87


1978
SER
OG
63.068
13.050
27.357
38.21


1979
VAL
N
63.544
13.269
24.191
26.20


1980
VAL
CA
62.453
13.223
23.204
23.76


1981
VAL
C
62.902
12.743
21.809
26.52


1982
VAL
O
63.645
13.435
21.074
28.45


1983
VAL
CB
61.667
14.568
23.186
25.58


1984
VAL
CG1
60.555
14.594
22.126
25.16


1985
VAL
CG2
61.053
14.793
24.553
24.66


1986
ASP
N
62.404
11.567
21.409
21.57


1987
ASP
CA
62.732
11.009
20.111
19.61


1988
ASP
C
61.521
11.154
19.182
26.16


1989
ASP
O
60.569
10.318
19.178
26.94


1990
ASP
CB
63.073
9.533
20.320
22.22


1991
ASP
CG
63.559
8.879
19.072
34.42


1992
ASP
OD1
63.392
9.325
17.935
28.99


1993
ASP
OD2
64.139
7.760
19.353
40.03


1994
ILE
N
61.550
12.245
18.381
23.48


1995
ILE
CA
60.414
12.608
17.503
19.92


1996
ILE
C
59.899
11.503
16.616
24.71


1997
ILE
O
58.701
11.191
16.558
22.68


1998
ILE
CB
60.775
13.880
16.762
20.09


1999
ILE
CG1
60.992
14.906
17.875
22.40


2000
ILE
CG2
59.660
14.316
15.820
17.07


2001
ILE
CD1
61.365
16.303
17.382
33.15


2002
LYS
N
60.844
10.882
15.909
20.78


2003
LYS
CA
60.402
9.864
14.960
21.92


2004
LYS
C
59.744
8.711
15.639
21.66


2005
LYS
O
58.801
8.086
15.176
24.06


2006
LYS
CB
61.517
9.349
14.047
22.87


2007
LYS
CG
62.275
10.451
13.370
20.42


2008
LYS
CD
63.483
9.834
12.671
33.57


2009
LYS
CE
64.772
10.122
13.443
43.45


2010
LYS
NZ
65.169
9.089
14.399
74.10


2011
LYS
N
60.328
8.382
16.736
19.22


2012
LYS
CA
59.802
7.275
17.481
21.33


2013
LYS
C
58.418
7.643
18.006
22.92


2014
LYS
O
57.563
6.767
18.082
18.47


2015
LYS
CB
60.804
6.907
18.595
26.85


2016
LYS
CG
60.510
5.641
19.360
57.18


2017
LYS
CD
61.693
5.220
20.236
74.44


2018
LYS
CE
61.283
4.289
21.393
100.00


2019
LYS
NZ
61.528
4.824
22.754
100.00


2020
VAL
N
58.209
8.943
18.386
20.32


2021
VAL
CA
56.880
9.344
18.869
19.06


2022
VAL
C
55.878
9.249
17.713
19.98


2023
VAL
O
54.733
8.767
17.821
19.01


2024
VAL
CB
56.868
10.755
19.474
21.25


2025
VAL
CG1
55.427
11.187
19.850
18.14


2026
VAL
CG2
57.734
10.742
20.750
21.39


2027
LEU
N
56.348
9.643
16.566
15.76


2028
LEU
CA
55.460
9.554
15.431
15.06


2029
LEU
C
55.086
8.101
15.149
21.46


2030
LEU
O
53.940
7.742
14.839
18.74


2031
LEU
CB
56.111
10.260
14.217
14.15


2032
LEU
CG
55.289
10.130
12.916
18.24


2033
LEU
CD1
53.915
10.764
13.092
16.76


2034
LEU
CD2
56.004
10.808
11.711
17.04


2035
LEU
N
56.064
7.209
15.275
20.58


2036
LEU
CA
55.762
5.798
15.021
18.54


2037
LEU
C
54.783
5.290
16.042
21.57


2038
LEU
O
53.935
4.472
15.713
22.28


2039
LEU
CB
57.015
4.889
14.955
19.53


2040
LEU
CG
57.819
5.029
13.630
24.40


2041
LEU
CD1
59.230
4.498
13.813
22.15


2042
LEU
CD2
57.127
4.319
12.437
21.17


2043
ASP
N
54.883
5.775
17.297
17.91


2044
ASP
CA
53.905
5.330
18.301
16.81


2045
ASP
C
52.538
5.845
17.897
19.40


2046
ASP
O
51.528
5.181
17.996
21.08


2047
ASP
CB
54.203
5.840
19.767
19.29


2048
ASP
CG
53.470
5.056
20.894
46.92


2049
ASP
OD1
53.626
3.832
21.196
39.76


2050
ASP
OD2
52.681
5.849
21.576
67.80


2051
MET
N
52.465
7.082
17.466
17.80


2052
MET
CA
51.146
7.550
17.093
18.08


2053
MET
C
50.586
6.785
15.902
19.16


2054
MET
O
49.360
6.544
15.802
19.67


2055
MET
CB
51.294
9.000
16.640
23.05


2056
MET
CG
51.750
9.946
17.756
33.10


2057
MET
SD
51.452
11.712
17.338
37.23


2058
MET
CE
50.717
12.236
18.903
32.15


2059
ARG
N
51.471
6.425
14.953
16.98


2060
ARG
CA
50.996
5.690
13.759
18.78


2061
ARG
C
50.448
4.309
14.082
20.60


2062
ARG
O
49.921
3.625
13.227
18.40


2063
ARG
CB
51.817
5.867
12.441
25.17


2064
ARG
CG
52.747
7.091
12.429
48.25


2065
ARG
CD
52.842
8.056
11.215
60.15


2066
ARG
NE
52.920
7.361
9.965
30.10


2067
ARG
CZ
53.076
7.701
8.652
25.89


2068
ARG
NH1
53.321
8.890
8.086
27.29


2069
ARG
NH2
53.031
6.649
7.819
19.72


2070
LYS
N
50.600
3.877
15.366
17.55


2071
LYS
CA
50.018
2.617
15.750
16.12


2072
LYS
C
48.516
2.808
15.804
23.50


2073
LYS
O
47.753
1.864
15.744
21.94


2074
LYS
CB
50.439
2.157
17.165
14.21


2075
LYS
CG
51.927
1.901
17.250
18.36


2076
LYS
CD
52.363
1.502
18.666
21.09


2077
LYS
CE
53.863
1.184
18.762
28.07


2078
LYS
NZ
54.278
1.049
20.179
30.77


2079
PHE
N
48.066
4.046
15.996
17.28


2080
PHE
CA
46.649
4.276
16.181
17.04


2081
PHE
C
45.896
4.765
14.955
19.33


2082
PHE
O
44.665
4.622
14.894
17.66


2083
PHE
CB
46.469
5.282
17.315
17.60


2084
PHE
CG
47.096
4.756
18.576
17.54


2085
PHE
CD1
46.372
3.897
19.407
19.62


2086
PHE
CD2
48.368
5.176
18.950
18.66


2087
PHE
CE1
46.943
3.369
20.570
21.35


2088
PHE
CE2
48.910
4.698
20.145
22.41


2089
PHE
CZ
48.214
3.787
20.946
19.04


2090
ARG
N
46.598
5.382
14.053
13.88


2091
ARG
CA
45.967
5.775
12.828
13.48


2092
ARG
C
47.051
5.809
11.774
16.22


2093
ARG
O
48.163
6.250
11.973
15.25


2094
ARG
CB
45.321
7.172
12.939
16.93


2095
ARG
CG
44.544
7.632
11.689
16.86


2096
ARG
CD
43.697
8.897
12.048
18.74


2097
ARG
NE
42.861
9.407
10.923
16.22


2098
ARG
CZ
41.658
8.932
10.504
27.02


2099
ARG
NH1
41.047
7.860
11.071
15.47


2100
ARG
NH2
41.056
9.547
9.443
17.92


2101
MET
N
46.715
5.395
10.564
18.09


2102
MET
CA
47.684
5.410
9.516
18.05


2103
MET
C
47.968
6.814
8.978
20.84


2104
MET
O
47.145
7.697
9.055
18.35


2105
MET
CB
47.079
4.556
8.343
19.02


2106
MET
CG
45.812
5.199
7.720
21.47


2107
MET
SD
45.180
4.334
6.222
26.31


2108
MET
CE
44.495
2.762
6.841
24.21


2109
GLY
N
49.125
6.961
8.363
15.59


2110
GLY
CA
49.540
8.083
7.529
18.21


2111
GLY
C
49.743
9.433
8.135
21.75


2112
GLY
O
49.791
10.451
7.402
18.48


2113
LEU
N
49.925
9.400
9.463
18.42


2114
LEU
CA
50.072
10.648
10.204
14.70


2115
LEU
C
51.314
11.339
9.720
18.00


2116
LEU
O
52.374
10.727
9.794
19.18


2117
LEU
CB
50.061
10.371
11.712
14.05


2118
LEU
CG
48.786
9.649
12.191
17.72


2119
LEU
CD1
48.869
9.460
13.706
17.55


2120
LEU
CD2
47.507
10.393
11.817
15.18


2121
ILE
N
51.159
12.596
9.295
15.02


2122
ILE
CA
52.219
13.420
8.703
15.09


2123
ILE
C
52.350
12.891
7.295
20.09


2124
ILE
O
52.785
11.728
7.088
16.03


2125
ILE
CB
53.538
13.451
9.423
17.27


2126
ILE
CG1
53.244
14.065
10.772
16.88


2127
ILE
CG2
54.476
14.391
8.650
17.72


2128
ILE
CD1
54.453
14.681
11.446
18.43


2129
GLN
N
51.917
13.710
6.331
18.36


2130
GLN
CA
51.887
13.223
4.941
19.19


2131
GLN
C
53.025
13.540
3.983
22.72


2132
GLN
O
53.040
13.026
2.871
20.09


2133
GLN
CB
50.522
13.582
4.326
19.65


2134
GLN
CG
49.371
12.674
4.858
22.65


2135
GLN
CD
49.367
11.349
4.113
26.84


2136
GLN
OE1
49.184
11.364
2.900
17.52


2137
GLN
NE2
49.600
10.236
4.801
19.94


2138
THR
N
53.911
14.414
4.397
21.73


2139
THR
CA
55.045
14.841
3.612
20.72


2140
THR
C
56.262
15.010
4.495
23.82


2141
THR
O
56.210
15.236
5.721
21.43


2142
THR
CB
54.876
16.140
2.852
21.33


2143
THR
CG1
55.050
17.211
3.777
23.48


2144
THR
CG2
53.520
16.222
2.174
16.62


2145
ALA
N
57.378
14.910
3.844
22.77


2146
ALA
CA
58.601
15.018
4.587
23.01


2147
ALA
C
58.801
16.403
5.105
22.21


2148
ALA
O
59.447
16.639
6.154
24.06


2149
ALA
CB
59.776
14.531
3.763
24.53


2150
ASP
N
58.259
17.354
4.370
20.66


2151
ASP
CA
58.422
18.724
4.858
20.24


2152
ASP
C
57.595
18.934
6.129
23.29


2153
ASP
O
57.899
19.740
7.024
23.21


2154
ASP
CB
58.049
19.778
3.806
23.48


2155
ASP
CG
58.591
21.167
4.207
30.38


2156
ASP
OD1
59.693
21.282
4.763
31.02


2157
ASP
OD2
57.785
22.190
3.885
34.64


2158
GLN
N
56.525
18.194
6.208
18.19


2159
GLN
CA
55.712
18.298
7.413
17.86


2160
GLN
C
56.513
17.759
8.615
23.26


2161
GLN
O
56.369
18.212
9.768
21.57


2162
GLN
CB
54.325
17.569
7.239
17.92


2163
GLN
CG
53.295
18.409
6.448
18.27


2164
GLN
CD
52.071
17.609
6.116
19.07


2165
GLN
OE1
52.036
16.389
6.390
18.84


2166
GLN
NE2
51.071
18.282
5.541
16.62


2167
LEU
N
57.349
16.727
8.369
20.85


2168
LEU
CA
58.148
16.126
9.423
17.29


2169
LEU
C
59.161
17.115
9.838
21.68


2170
LEU
O
59.368
17.386
11.015
21.08


2171
LEU
CB
58.770
14.818
8.982
16.92


2172
LEU
CG
59.679
14.141
10.018
18.94


2173
LEU
CD1
58.866
13.624
11.231
17.31


2174
LEU
CD2
60.409
12.959
9.351
15.70


2175
ARG
N
59.781
17.705
8.820
20.27


2176
ARG
CA
60.792
18.727
9.101
19.02


2177
ARG
C
60.181
19.859
9.932
22.20


2178
ARG
O
60.689
20.361
10.947
21.23


2179
ARG
CB
61.327
19.293
7.792
15.51


2180
ARG
CG
62.568
20.163
8.046
21.78


2181
ARG
CD
63.127
20.785
6.770
27.88


2182
ARG
NE
64.351
21.523
7.038
33.02


2183
ARG
CZ
64.355
22.814
7.227
31.22


2184
ARG
NH1
63.242
23.517
7.186
23.06


2185
ARG
NH2
65.508
23.412
7.478
31.35


2186
PHE
N
59.007
20.291
9.471
20.79


2187
PHE
CA
58.378
21.345
10.214
18.33


2188
PHE
C
58.180
20.945
11.680
23.47


2189
PHE
O
58.375
21.746
12.588
22.26


2190
PHE
CB
57.065
21.789
9.582
16.79


2191
PHE
CG
56.399
22.920
10.381
21.31


2192
PHE
CD1
56.681
24.267
10.126
21.18


2193
PHE
CD2
55.431
22.654
11.355
21.09


2194
PHE
CE1
56.063
25.309
10.814
22.40


2195
PHE
CE2
54.836
23.698
12.074
22.51


2196
PHE
CZ
55.164
25.025
11.833
19.57


2197
SER
N
57.752
19.714
11.884
20.57


2198
SER
CA
57.496
19.183
13.233
19.79


2199
SER
C
58.704
19.438
14.082
22.01


2200
SER
O
58.617
19.894
15.216
21.53


2201
SER
CB
57.252
17.666
13.231
16.35


2202
SER
OG
55.984
17.531
12.733
31.09


2203
TYR
N
59.841
19.086
13.544
20.69


2204
TYR
CA
61.030
19.291
14.365
19.51


2205
TYR
C
61.207
20.766
14.689
21.92


2206
TYR
O
61.557
21.130
15.818
20.31


2207
TYR
CB
62.273
18.913
13.583
19.52


2208
TYR
CG
62.654
17.464
13.682
24.16


2209
TYR
CD1
61.877
16.472
13.074
24.17


2210
TYR
CD2
63.872
17.095
14.281
26.60


2211
TYR
CE1
62.245
15.126
13.119
24.68


2212
TYR
CE2
64.261
15.750
14.311
25.92


2213
TYR
CZ
63.440
14.771
13.749
24.97


2214
TYR
OH
63.827
13.469
13.819
32.37


2215
LEU
N
60.985
21.623
13.670
19.51


2216
LEU
CA
61.150
23.020
13.916
17.52


2217
LEU
C
60.225
23.486
15.031
26.06


2218
LEU
O
60.606
24.304
15.892
25.65


2219
LEU
CB
60.860
23.865
12.721
16.93


2220
LEU
CG
61.898
23.718
11.592
26.47


2221
LEU
CD1
61.535
24.606
10.412
24.45


2222
LEU
CD2
63.302
24.080
12.029
28.00


2223
ALA
N
58.990
23.004
15.018
19.08


2224
ALA
CA
58.051
23.437
16.041
16.99


2225
ALA
C
58.424
22.901
17.408
20.57


2226
ALA
O
58.287
23.551
18.424
19.60


2227
ALA
CB
56.587
23.121
15.708
16.41


2228
VAL
N
58.905
21.698
17.488
17.68


2229
VAL
CA
59.206
21.230
18.835
17.05


2230
VAL
C
60.448
21.893
19.395
23.15


2231
VAL
O
60.592
22.155
20.616
21.24


2232
VAL
CB
59.378
19.694
18.826
20.45


2233
VAL
CG1
59.865
19.096
20.165
18.27


2234
VAL
CG2
58.084
19.006
18.357
19.14


2235
ILE
N
61.405
22.100
18.504
21.22


2236
ILE
CA
62.661
22.702
18.937
20.04


2237
ILE
C
62.420
24.090
19.475
25.88


2238
ILE
O
62.999
24.462
20.493
25.47


2239
ILE
CB
63.639
22.794
17.766
24.05


2240
ILE
CG1
64.232
21.403
17.511
25.87


2241
ILE
CG2
64.736
23.758
18.113
22.69


2242
ILE
CD1
64.839
21.250
16.118
27.49


2243
GLU
N
61.577
24.877
18.781
19.27


2244
GLU
CA
61.260
26.237
19.213
17.92


2245
GLU
C
60.385
26.224
20.480
22.75


2246
GLU
O
60.556
27.020
21.388
20.84


2247
GLU
CB
60.510
26.936
18.054
19.09


2248
GLU
CG
59.998
28.359
18.389
20.36


2249
GLU
CD
61.125
29.327
18.744
29.49


2250
GLU
OE1
62.316
29.183
18.463
23.96


2251
GLU
OE2
60.693
30.344
19.428
26.29


2252
GLY
N
59.423
25.296
20.515
20.31


2253
GLY
CA
58.498
25.189
21.643
18.63


2254
GLY
C
59.259
24.833
22.907
23.95


2255
GLY
O
58.870
25.127
24.072
18.97


2256
ALA
N
60.356
24.110
22.677
23.58


2257
ALA
CA
61.188
23.677
23.804
23.19


2258
ALA
C
61.565
24.862
24.682
23.67


2259
ALA
O
61.732
24.708
25.900
25.14


2260
ALA
CB
62.471
22.961
23.330
23.30


2261
LYS
N
61.747
26.038
24.042
19.35


2262
LYS
CA
62.155
27.232
24.809
19.49


2263
LYS
C
61.196
27.564
25.955
25.32


2264
LYS
O
61.575
27.937
27.090
22.02


2265
LYS
CB
62.225
28.423
23.883
21.56


2266
LYS
CG
63.349
28.249
22.857
24.29


2267
LYS
CD
63.327
29.437
21.907
28.63


2268
LYS
CE
64.359
29.447
20.820
33.79


2269
LYS
NZ
63.978
30.470
19.839
63.50


2270
PHE
N
59.922
27.482
25.608
20.00


2271
PHE
CA
58.858
27.740
26.571
17.26


2272
PHE
C
58.834
26.622
27.598
23.66


2273
PHE
O
58.789
26.847
28.791
23.24


2274
PHE
CB
57.543
27.740
25.772
19.05


2275
PHE
CG
56.407
27.958
26.718
23.90


2276
PHE
CD1
55.800
26.859
27.315
30.06


2277
PHE
CD2
56.014
29.242
27.087
25.49


2278
PHE
CE1
54.788
27.010
28.262
31.06


2279
PHE
CE2
54.982
29.400
28.015
30.43


2280
PHE
CZ
54.380
28.294
28.612
28.57


2281
ILE
N
58.841
25.369
27.139
21.16


2282
ILE
CA
58.815
24.235
28.070
21.71


2283
ILE
C
60.001
24.330
29.014
26.83


2284
ILE
O
59.949
23.959
30.185
28.05


2285
ILE
CB
59.014
22.890
27.335
24.04


2286
ILE
CG1
57.843
22.495
26.446
24.85


2287
ILE
CG2
59.269
21.758
28.309
26.71


2288
ILE
CD1
56.488
23.121
26.760
22.80


2289
MET
N
61.117
24.785
28.524
21.30


2290
MET
CA
62.205
24.825
29.440
23.12


2291
MET
C
62.325
26.098
30.299
28.91


2292
MET
O
63.398
26.410
30.748
31.20


2293
MET
CB
63.520
24.378
28.836
25.89


2294
MET
CG
63.303
23.037
28.171
29.97


2295
MET
SD
63.168
21.686
29.352
29.79


2296
MET
CE
64.744
21.950
30.149
26.41


2297
GLY
N
61.278
26.868
30.528
24.26


2298
GLY
CA
61.489
27.964
31.450
24.71


2299
GLY
C
61.414
29.354
30.933
25.55


2300
GLY
O
61.441
30.290
31.708
24.08


2301
ASP
N
61.338
29.535
29.658
21.90


2302
ASP
CA
61.207
30.919
29.246
22.03


2303
ASP
C
59.786
31.173
28.742
27.04


2304
ASP
O
59.433
31.017
27.567
29.25


2305
ASP
CB
62.264
31.272
28.189
25.34


2306
ASP
CG
62.034
32.645
27.603
36.54


2307
ASP
OD1
61.228
33.466
28.063
40.88


2308
ASP
OD2
62.728
32.823
26.512
33.74


2309
SER
N
58.906
31.542
29.605
24.08


2310
SER
CA
57.570
31.757
29.101
26.04


2311
SER
C
57.474
32.994
28.153
33.52


2312
SER
O
56.550
33.100
27.360
33.01


2313
SER
CB
56.523
31.840
30.246
28.08


2314
SER
OG
56.595
30.689
31.114
27.62


2315
SER
N
58.412
33.948
28.264
28.61


2316
SER
CA
58.379
35.156
27.472
26.34


2317
SER
C
58.298
34.830
25.956
32.58


2318
SER
O
57.816
35.629
25.094
30.04


2319
SER
CB
59.651
35.942
27.768
22.72


2320
SER
OG
60.712
35.599
26.864
34.10


2321
VAL
N
58.812
33.647
25.599
28.26


2322
VAL
CA
58.797
33.246
24.170
28.99


2323
VAL
C
57.356
33.239
23.563
32.46


2324
VAL
O
57.093
33.549
22.403
28.95


2325
VAL
CB
59.628
31.965
23.969
29.56


2326
VAL
CG1
58.841
30.740
24.349
27.83


2327
VAL
CG2
60.017
31.836
22.548
31.39


2328
GLN
N
56.370
32.942
24.425
30.24


2329
GLN
CA
54.974
32.874
24.017
29.27


2330
GLN
C
54.503
34.187
23.477
30.84


2331
GLN
O
53.777
34.236
22.506
27.71


2332
GLN
CB
54.073
32.406
25.207
32.06


2333
GLN
CG
52.561
32.481
24.958
56.39


2334
GLN
CD
51.805
31.561
25.885
51.02


2335
GLN
OE1
52.229
31.337
27.004
34.74


2336
GLN
NE2
50.703
31.010
25.403
62.41


2337
ASP
N
54.895
35.262
24.140
29.32


2338
ASP
CA
54.505
36.602
23.691
30.87


2339
ASP
C
55.136
36.911
22.333
30.01


2340
ASP
O
54.530
37.499
21.433
31.24


2341
ASP
CB
54.906
37.629
24.756
35.79


2342
ASP
CG
54.358
37.219
26.082
65.63


2343
ASP
OD1
53.170
36.998
26.227
71.17


2344
ASP
OD2
55.278
37.034
27.014
80.27


2345
GLN
N
56.374
36.460
22.194
25.78


2346
GLN
CA
57.108
36.574
20.948
26.06


2347
GLN
C
56.384
35.851
19.806
30.03


2348
GLN
O
56.246
36.357
18.715
26.89


2349
GLN
CB
58.455
35.924
21.120
27.67


2350
GLN
CG
59.317
36.611
22.198
44.36


2351
GLN
CD
60.751
36.116
22.147
77.73


2352
GLN
OE1
61.283
35.846
21.053
88.38


2353
GLN
NE2
61.357
35.952
23.326
61.19


2354
TRP
N
55.906
34.644
20.070
26.22


2355
TRP
CA
55.195
33.953
19.048
23.95


2356
TRP
C
53.959
34.709
18.716
27.74


2357
TRP
O
53.590
34.825
17.557
29.34


2358
TRP
CB
54.752
32.529
19.487
22.50


2359
TRP
CG
55.887
31.639
19.847
21.30


2360
TRP
CD1
57.167
31.756
19.417
23.75


2361
TRP
CD2
55.842
30.526
20.763
19.48


2362
TRP
NE1
57.927
30.767
19.994
23.42


2363
TRP
CE2
57.143
30.005
20.849
22.89


2364
TRP
CE3
54.820
29.939
21.517
20.00


2365
TRP
CZ2
57.464
28.895
21.668
20.62


2366
TRP
CZ3
55.119
28.829
22.299
20.58


2367
TRP
CH2
56.418
28.303
22.365
20.81


2368
LYS
N
53.273
35.191
19.732
25.02


2369
LYS
CA
52.051
35.913
19.449
23.72


2370
LYS
C
52.279
37.141
18.512
32.33


2371
LYS
O
51.536
37.430
17.531
28.38


2372
LYS
CB
51.390
36.292
20.731
24.86


2373
LYS
CG
50.049
36.954
20.489
36.15


2374
LYS
CD
49.612
37.791
21.672
56.07


2375
LYS
CE
48.105
37.986
21.748
94.91


2376
LYS
NZ
47.664
38.697
22.968
100.00


2377
GLU
N
53.319
37.895
18.808
32.11


2378
GLU
CA
53.630
39.036
17.969
35.38


2379
GLU
C
54.028
38.602
16.559
36.31


2380
GLU
O
53.557
39.097
15.540
38.26


2381
GLU
CB
54.813
39.855
18.548
39.32


2382
GLU
CG
54.559
40.416
19.974
69.72


2383
GLU
CD
53.542
41.540
19.993
100.00


2384
GLU
OE1
53.826
42.742
19.907
100.00


2385
GLU
OE2
52.311
41.071
20.086
100.00


2386
LEU
N
54.930
37.668
16.477
29.59


2387
LEU
CA
55.371
37.218
15.175
29.45


2388
LEU
C
54.297
36.602
14.316
34.02


2389
LEU
O
54.438
36.402
13.095
34.53


2390
LEU
CB
56.402
36.124
15.389
30.02


2391
LEU
CG
57.673
36.730
15.958
37.18


2392
LEU
CD1
58.611
35.621
16.448
36.22


2393
LEU
CD2
58.332
37.541
14.834
39.33


2394
SER
N
53.238
36.196
14.951
26.99


2395
SER
CA
52.226
35.561
14.179
27.01


2396
SER
C
51.217
36.583
13.608
33.85


2397
SER
O
50.359
36.208
12.843
33.74


2398
SER
CB
51.521
34.632
15.134
28.99


2399
SER
OG
50.444
35.407
15.648
44.35


2400
HIS
N
51.275
37.855
14.034
33.50


2401
HIS
CA
50.355
38.935
13.604
36.33


2402
HIS
C
48.945
38.510
13.663
34.53


2403
HIS
O
48.221
38.641
12.668
29.05


2404
HIS
CB
50.574
39.458
12.177
41.53


2405
HIS
CG
52.003
39.597
11.966
50.56


2406
HIS
ND1
52.683
38.801
11.043
55.72


2407
HIS
CD2
52.889
40.377
12.656
55.69


2408
HIS
CE1
53.978
39.152
11.158
56.62


2409
HIS
NE2
54.131
40.085
12.120
56.78


2410
GLU
N
48.528
38.023
14.795
31.47


2411
GLU
CA
47.172
37.560
14.773
32.57


2412
GLU
C
46.110
38.585
14.659
35.60


2413
GLU
O
44.984
38.253
14.397
35.07


2414
GLU
CB
46.886
36.568
15.881
34.05


2415
GLU
CG
47.343
37.124
17.210
29.10


2416
GLU
CD
46.766
36.272
18.291
44.34


2417
GLU
OE1
46.803
35.044
18.311
28.10


2418
GLU
OE2
46.156
36.987
19.183
42.70


2419
ASP
N
46.433
39.851
14.841
38.45


2420
ASP
CA
45.375
40.870
14.777
78.44


2421
ASP
C
45.114
41.525
13.428
73.26


2422
ASP
O
46.027
41.652
12.620
57.37


2423
ASP
CB
45.440
41.851
15.949
80.14


2424
ASP
CG
45.045
41.139
17.215
99.39


2425
ASP
OD1
43.981
40.514
17.333
100.00


2426
ASP
OD2
45.979
41.210
18.148
100.00


2427
HOH
O
38.401
17.896
24.639
19.06


2428
HOH
O
42.880
−2.994
13.734
22.22


2429
HOH
O
37.909
0.024
10.420
18.06


2430
HOH
O
34.283
3.652
13.551
16.99


2431
HOH
O
31.031
7.792
20.003
21.22


2432
HOH
O
56.762
16.414
35.819
23.22


2433
HOH
O
38.520
4.591
3.340
17.34


2434
HOH
O
38.706
8.875
4.448
19.05


2435
HOH
O
48.541
17.369
4.500
18.16


2436
HOH
O
22.375
24.091
20.022
27.04


2437
HOH
O
50.383
3.090
10.757
19.44


2438
HOH
O
56.581
20.545
34.028
23.47


2439
HOH
O
44.023
22.433
27.502
26.90


2440
HOH
O
23.678
29.248
15.041
26.35


2441
HOH
O
30.955
16.693
24.220
25.48


2442
HOH
O
36.539
−2.273
15.479
27.62


2443
HOH
O
60.199
22.714
6.928
25.25


2444
HOH
O
42.799
15.905
24.284
24.08


2445
HOH
O
58.854
31.126
13.755
28.34


2446
HOH
O
25.489
12.276
9.898
29.35


2447
HOH
O
44.868
21.909
30.537
27.95


2448
HOH
O
19.794
30.078
16.536
27.05


2449
HOH
O
41.421
3.661
14.164
17.35


2450
HOH
O
41.884
2.616
3.383
21.00


2451
HOH
O
34.858
3.969
20.688
28.33


2452
HOH
O
53.734
2.425
13.962
22.10


2453
HOH
O
60.930
9.816
23.103
29.63


2454
HOH
O
42.886
3.496
20.674
24.24


2455
HOH
O
30.810
36.766
18.288
26.91


2456
HOH
O
59.810
32.233
32.172
26.16


2457
HOH
O
57.738
17.405
1.262
32.83


2458
HOH
O
36.660
27.108
5.425
23.54


2459
HOH
O
32.265
17.633
1.767
24.56


2460
HOH
O
66.198
17.107
2.407
38.58


2461
HOH
O
57.752
28.197
31.074
29.94


2462
HOH
O
41.286
15.987
26.904
32.37


2463
HOH
O
36.669
27.749
2.270
31.44


2464
HOH
O
39.624
−4.625
16.505
28.88


2465
HOH
O
45.398
24.023
0.668
27.71


2466
HOH
O
51.673
32.445
21.771
23.43


2467
HOH
O
53.099
24.833
2.471
29.74


2468
HOH
O
54.526
19.450
2.810
28.76


2469
HOH
O
27.105
36.172
19.570
24.82


2470
HOH
O
36.334
30.259
9.265
30.82


2471
HOH
O
56.626
24.387
33.815
30.17


2472
HOH
O
42.738
29.954
24.494
35.73


2473
HOH
O
57.220
13.971
0.977
32.27


2474
HOH
O
65.256
29.469
30.089
39.20


2475
HOH
O
49.786
39.709
16.909
43.80


2476
HOH
O
52.863
6.253
24.788
35.18


2477
HOH
O
35.798
−5.535
5.469
31.13


2478
HOH
O
50.331
22.923
−0.657
36.76


2479
HOH
O
36.765
3.406
1.739
42.22


2480
HOH
O
26.434
4.890
5.483
35.83


2481
HOH
O
34.613
32.955
20.594
43.11


2482
HOH
O
27.837
3.167
1.403
42.94


2483
HOH
O
32.582
9.372
−0.315
36.58


2484
HOH
O
45.800
3.147
2.702
31.42


2485
HOH
O
33.763
0.985
2.765
30.40


2486
HOH
O
29.040
1.300
20.110
50.77


2487
HOH
O
42.199
−4.222
6.234
38.97


2488
HOH
O
21.619
20.058
9.321
40.28


2489
HOH
O
53.500
20.656
27.642
27.42


2490
HOH
O
16.860
27.164
18.394
26.90


2491
HOH
O
43.874
0.861
20.343
25.50


2492
HOH
O
29.683
−0.569
10.390
26.21


2493
HOH
O
28.054
11.908
26.787
41.40


2494
HOH
O
50.466
28.546
28.067
42.56


2495
HOH
O
28.502
21.053
3.156
30.33


2496
HOH
O
63.942
27.419
17.604
28.20


2497
HOH
O
22.109
21.232
30.110
48.48


2498
HOH
O
49.254
32.003
23.342
40.08


2499
HOH
O
24.641
7.692
4.830
53.24


2500
HOH
O
63.797
11.089
16.405
27.62


2501
HOH
O
53.333
9.033
24.881
28.87


2502
HOH
O
37.700
0.242
19.127
49.32


2503
HOH
O
24.665
29.142
9.720
48.36


2504
HOH
O
54.352
−3.114
9.194
44.58


2505
HOH
O
62.631
5.916
11.920
39.76


2506
HOH
O
63.952
28.080
27.641
38.19


2507
HOH
O
65.802
19.783
33.411
38.59


2508
HOH
O
57.255
27.489
7.852
41.05


2509
HOH
O
19.030
25.560
24.767
57.85


2510
HOH
O
64.201
13.583
18.348
29.38


2511
HOH
O
55.852
−0.427
22.999
50.13


2512
HOH
O
36.898
−5.489
16.055
67.33


2513
HOH
O
33.905
27.753
6.095
27.01


2514
HOH
O
27.382
−1.372
13.747
35.80


2515
HOH
O
33.489
−3.895
15.708
41.00


2516
HOH
O
24.559
2.258
7.150
41.23


2517
HOH
O
65.779
15.180
21.392
35.84


2518
HOH
O
65.553
25.125
21.639
47.37


2519
HOH
O
32.513
19.611
26.519
62.17


2520
HOH
O
33.651
17.294
28.933
55.49


2521
HOH
O
41.137
19.611
−7.004
52.94


2522
HOH
O
66.395
21.128
4.224
47.91


2523
HOH
O
23.251
11.180
19.061
48.42


2524
HOH
O
39.259
33.229
22.025
51.45


2525
HOH
O
36.119
32.908
9.928
44.34


2526
HOH
O
53.725
36.111
5.937
100.00


2527
HOH
O
63.179
35.153
24.999
55.42


2528
HOH
O
35.968
6.586
−0.582
43.18


2529
HOH
O
21.346
7.913
13.010
56.07


2530
HOH
O
19.175
28.875
19.382
53.38


2531
HOH
O
22.715
7.898
10.565
50.52


2532
HOH
O
47.395
34.116
21.423
47.24


2533
HOH
O
32.765
7.633
26.983
64.04


2534
HOH
O
54.471
34.005
11.028
47.55


2535
HOH
O
72.465
12.809
15.523
46.13


2536
HOH
O
47.441
6.136
−1.870
46.53


2537
HOH
O
43.416
18.301
−3.456
49.44


2538
HOH
O
65.579
21.420
21.981
50.95


2539
HOH
O
47.751
7.411
2.407
40.84


2540
HOH
O
32.644
8.712
8.756
15.74


2541
HOH
O
33.023
11.570
8.792
15.03


2542
HOH
O
44.089
25.927
7.019
19.82


2543
HOH
O
58.775
26.249
32.830
26.89


2544
HOH
O
51.112
4.543
8.642
20.55


2545
HOH
O
62.946
25.839
15.605
26.99


2546
HOH
O
40.881
−6.288
14.710
22.12


2547
HOH
O
52.351
8.308
5.018
25.66


2548
HOH
O
61.224
24.419
33.190
30.44


2549
HOH
O
28.243
−3.909
4.213
32.48


2550
HOH
O
62.221
27.938
13.810
30.53


2551
HOH
O
39.610
−6.610
12.431
30.17


2552
HOH
O
54.043
16.770
35.701
34.80


2553
HOH
O
15.219
28.439
20.359
31.31


2554
HOH
O
64.424
20.767
35.354
32.43


2555
HOH
O
14.987
23.468
24.936
33.81


2556
HOH
O
21.319
29.054
23.219
34.70


2557
HOH
O
30.027
−1.696
12.465
39.40


2558
HOH
O
25.366
15.033
7.774
33.88


2559
HOH
O
66.346
11.979
1.208
42.20


2560
HOH
O
17.665
23.698
26.769
54.87


2561
HOH
O
51.859
5.861
4.981
38.52


2562
HOH
O
24.749
29.791
25.560
42.21


2563
HOH
O
57.813
3.867
18.815
41.01


2564
HOH
O
63.315
26.715
7.503
46.17


2565
HOH
O
53.229
27.524
4.226
50.52


2566
HOH
O
63.148
7.825
9.883
44.30


2567
HOH
O
26.879
19.362
7.236
22.65


2568
HOH
O
67.878
17.615
34.499
44.34


2569
HOH
O
54.054
30.226
31.561
25.96


2570
HOH
O
54.931
12.873
0.470
42.81


2571
HOH
O
44.558
8.294
−3.296
70.17


2572
HOH
O
26.495
26.387
25.981
49.19


2573
HOH
O
45.561
9.651
27.926
47.40


2574
HOH
O
33.903
−6.440
2.953
64.63


2575
HOH
O
64.772
6.818
21.874
47.22


2576
HOH
O
38.599
3.739
20.598
47.72


2577
HOH
O
40.578
33.268
10.218
43.71


2578
HOH
O
23.004
14.669
9.548
41.06


2579
HOH
O
18.520
21.210
10.100
82.04


2580
HOH
O
54.443
0.368
6.856
46.46


2581
HOH
O
53.301
3.094
5.341
55.82


2582
HOH
O
62.577
30.234
15.315
50.03


2583
HOH
O
58.940
24.723
5.711
51.05


2584
HOH
O
20.726
3.366
15.601
78.38


2585
HOH
O
43.027
13.430
27.118
54.39


2586
HOH
O
62.195
28.464
10.795
46.23


2587
HOH
O
50.510
34.226
10.824
39.07


2588
HOH
O
40.918
−2.815
21.009
65.28


2589
HOH
O
43.587
26.925
−2.428
47.56


2590
HOH
O
13.754
15.204
18.843
53.86


2591
HOH
O
31.164
30.490
3.629
56.80


2592
HOH
O
64.794
14.809
1.227
46.20


2593
HOH
O
65.739
6.902
9.576
42.14


2594
HOH
O
22.779
9.377
7.806
74.52


2595
HOH
O
35.536
1.247
20.572
58.11


2596
HOH
O
48.720
41.298
14.904
65.02


2597
HOH
O
41.886
8.125
26.131
43.72


2598
HOH
O
21.553
25.706
8.779
67.26


2599
HOH
O
47.438
24.713
−1.762
68.04


2600
HOH
O
59.462
2.577
16.912
44.01


2601
HOH
O
34.650
13.050
10.584
15.74


2602
HOH
O
44.151
3.876
10.554
20.85


2603
HOH
O
30.226
8.145
9.680
20.38


2604
HOH
O
50.795
5.197
23.429
23.53


2605
HOH
O
55.241
24.256
1.478
43.03


2606
HOH
O
13.876
26.053
19.951
39.87


2607
HOH
O
37.440
7.794
22.997
34.34


2608
HOH
O
36.776
4.942
22.481
44.54


2609
HOH
O
49.204
6.833
4.042
59.47


2610
HOH
O
46.016
15.869
28.666
53.22


2611
HOH
O
52.597
14.225
35.410
44.55


2612
HOH
O
55.717
8.332
23.770
40.53


2613
HOH
O
35.617
38.541
15.729
45.63


2614
HOH
O
24.347
36.908
13.597
48.19


2615
HOH
O
37.734
23.590
30.260
62.04


2616
HOH
O
59.359
7.814
23.351
51.17


2617
HOH
O
40.870
−8.615
10.301
39.22


2618
HOH
O
55.653
−1.953
5.995
52.57


2619
HOH
O
51.582
1.831
22.838
43.21


2620
HOH
O
23.536
16.687
3.287
66.26


2621
HOH
O
27.390
9.583
26.222
66.80


2622
HOH
O
26.006
26.772
7.979
55.20


2623
HOH
O
48.629
36.281
9.258
53.85


2624
HOH
O
54.312
1.731
24.312
49.12


2625
HOH
O
64.534
7.113
16.407
42.12


2626
HOH
O
43.617
30.982
3.143
48.34


2627
HOH
O
22.572
13.132
27.363
70.18


2628
HOH
O
70.408
21.965
2.674
89.51


2629
HOH
O
63.931
33.405
22.517
55.19


2630
HOH
O
48.600
32.735
29.774
71.55


2631
HOH
O
34.250
14.917
30.699
46.61


2632
HOH
O
43.731
33.337
6.158
93.58


2633
HOH
O
60.489
31.207
10.548
55.19


2634
HOH
O
50.155
2.150
6.615
54.57


2635
HOH
O
25.514
6.559
24.332
75.79


2636
HOH
O
31.745
30.209
9.802
50.27


2637
HOH
O
35.679
10.169
26.838
65.87


2638
HOH
O
13.764
16.372
28.336
78.20


2639
HOH
O
17.554
19.418
30.248
64.92


2640
HOH
O
65.875
16.089
34.874
64.83


2641
HOH
O
68.340
17.620
27.806
60.04


2642
HOH
O
36.275
32.819
22.710
48.84


2643
HOH
O
63.468
8.121
24.078
51.50


2644
HOH
O
39.850
34.128
24.551
67.42


2645
HOH
O
22.019
12.665
7.060
70.82


2646
HOH
O
30.890
−4.164
13.154
65.28


2647
HOH
O
23.362
5.115
3.428
51.03


2648
HOH
O
41.079
12.774
28.276
77.64


2649
HOH
O
32.157
37.768
15.682
60.54


2650
HOH
O
37.346
12.911
33.109
69.06


2651
HOH
O
60.400
−0.560
17.559
60.23


1
95
C1
45.324
12.023
1.856
20.00


2
95
S2
45.841
12.927
3.269
20.00


3
95
C3
44.986
14.367
2.692
20.00


4
95
C4
44.391
14.159
1.498
20.00


5
95
C5
44.709
12.824
0.981
20.00


6
95
N6
44.964
15.620
3.482
20.00


7
95
C7
45.489
15.733
4.720
20.00


8
95
C8
45.238
16.996
5.547
20.00


9
95
O9
44.228
17.659
5.375
20.00


10
95
O10
45.978
17.336
6.420
20.00


11
95
O11
46.159
14.860
5.251
20.00


12
95
C12
43.503
15.119
0.776
20.00


13
95
O13
43.428
15.102
−0.452
20.00


14
95
O14
42.803
15.898
1.358
20.00


15
95
C18
44.232
12.358
−0.368
20.00


16
95
C19
44.430
10.836
−0.521
20.00


17
95
N20
45.675
10.345
0.087
20.00


18
95
C21
45.756
10.616
1.531
20.00
















TABLE B







Table of the orthogonal three dimensional coordinates in Ångstroms and B


factors (Å2) for Protein Tyrosine Phosphatase 1B complexed with


7-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-


amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid


(Example 26).












No
Amino acid
X
Y
Z
B
















1
GLU
N
39.465
52.977
54.384
50.84


2
GLU
CA
38.798
51.719
54.051
51.38


3
GLU
C
39.109
51.267
52.590
49.72


4
GLU
O
38.944
52.002
51.620
49.04


5
GLU
GB
37.270
51.855
54.252
53.79


6
GLU
CG
36.557
50.495
54.416
57.54


7
GLU
CD
36.972
49.698
55.707
62.60


8
GLU
OE1
36.770
50.216
56.799
64.63


9
GLU
OE2
37.518
48.585
55.616
64.40


10
MET
N
39.495
49.971
52.496
46.10


11
MET
CA
39.753
49.178
51.264
42.61


12
MET
C
38.547
49.091
50.363
40.49


13
MET
O
38.640
48.979
49.159
38.08


14
MET
CB
40.128
47.730
51.640
41.62


15
MET
CG
39.190
47.107
52.716
40.45


16
MET
SD
39.645
45.471
53.299
35.84


17
MET
CE
41.295
45.867
53.958
39.51


18
GLU
N
37.419
49.189
51.051
40.04


19
GLU
CA
36.086
49.198
50.457
41.99


20
GLU
C
35.767
50.510
49.639
41.64


21
GLU
O
35.409
50.486
48.472
42.33


22
GLU
CB
35.156
48.876
51.627
43.82


23
GLU
CG
33.862
48.113
51.292
47.17


24
GLU
CD
33.244
47.563
52.607
49.31


25
GLU
OE1
33.732
47.923
53.672
48.56


26
GLU
OE2
32.301
46.761
52.564
51.19


27
LYS
N
36.000
51.696
50.213
40.99


28
LYS
CA
35.753
52.839
49.308
41.50


29
LYS
C
36.854
52.957
48.192
39.57


30
LYS
O
36.534
53.231
47.054
39.12


31
LYS
GB
35.643
54.142
50.104
45.89


32
LYS
CG
34.578
54.185
51.248
51.71


33
LYS
CD
35.008
55.173
52.386
56.13


34
LYS
CE
34.450
54.867
53.793
59.81


35
LYS
NZ
35.323
55.409
54.876
62.35


36
GLU
N
38.147
52.704
48.526
38.42


37
GLU
CA
39.236
52.572
47.517
37.30


38
GLU
C
38.888
51.620
46.385
34.58


39
GLU
O
39.054
51.964
45.238
33.74


40
GLU
CB
40.601
52.140
48.101
40.63


41
GLU
CG
41.526
51.508
47.019
46.16


42
GLU
CD
43.077
51.484
47.114
49.22


43
GLU
OE1
43.672
50.792
47.941
50.86


44
GLU
OE2
43.723
52.146
46.288
51.79


45
PHE
N
38.395
50.433
46.755
31.46


46
PHE
CA
37.835
49.488
45.799
30.49


47
PHE
C
36.777
50.107
44.857
33.05


48
PHE
O
36.828
49.954
43.648
31.17


49
PHE
CB
37.148
48.330
46.531
26.00


50
PHE
CG
36.682
47.268
45.560
23.39


51
PHE
CD1
37.608
46.321
45.069
24.75


52
PHE
CD2
35.388
47.202
45.084
23.83


53
PHE
CE1
37.277
45.364
44.109
21.69


54
PHE
CE2
35.064
46.263
44.099
23.15


55
PHE
CZ
35.985
45.348
43.603
22.50


56
GLU
N
35.818
50.823
45.452
34.78


57
GLU
CA
34.725
51.349
44.619
36.92


58
GLU
C
35.092
52.587
43.702
34.88


59
GLU
O
34.771
52.673
42.529
34.89


60
GLU
CB
33.592
51.542
45.609
42.69


61
GLU
CG
33.191
50.163
46.129
51.81


62
GLU
CD
32.044
50.199
47.121
58.22


63
GLU
OE1
31.735
51.274
47.661
60.76


64
GLU
OE2
31.467
49.123
47.337
60.88


65
GLN
N
35.875
53.523
44.252
32.17


66
GLN
CA
36.614
54.515
43.493
32.79


67
GLN
C
37.270
53.878
42.281
32.59


68
GLN
O
37.068
54.411
41.198
33.38


69
GLN
CB
37.684
55.103
44.398
38.01


70
GLN
CG
38.460
56.386
44.041
46.72


71
GLN
CD
39.538
56.621
45.198
54.60


72
GLN
CE1
40.705
56.281
45.103
58.48


73
GLN
NE2
39.104
57.129
46.335
57.65


74
ILE
N
37.995
52.752
42.495
30.75


75
ILE
CA
38.784
52.110
41.427
29.79


76
ILE
C
37.944
51.513
40.345
29.61


77
ILE
O
38.222
51.644
39.164
28.92


78
ILE
CB
39.820
51.020
41.780
28.01


79
ILE
CG1
40.944
51.578
42.625
26.65


80
ILE
CG2
40.547
50.559
40.485
24.67


81
ILE
CD1
41.717
50.482
43.321
30.61


82
ASP
N
36.941
50.841
40.826
30.56


83
ASP
CA
36.056
50.131
39.941
34.30


84
ASP
C
35.275
51.174
39.066
36.61


85
ASP
O
35.220
51.032
37.847
37.72


86
ASP
CB
35.183
49.189
40.820
34.23


87
ASP
CG
35.372
47.692
40.610
34.09


88
ASP
OD1
36.406
47.266
40.156
34.45


89
ASP
OD2
34.468
46.917
40.892
35.24


90
LYS
N
34.750
52.271
39.708
38.57


91
LYS
CA
34.018
53.296
38.901
40.78


92
LYS
C
34.892
53.932
37.806
40.89


93
LYS
O
34.499
54.071
36.665
41.19


94
LYS
CB
33.321
54.430
39.687
44.73


95
LYS
CG
34.160
55.716
39.765
49.46


96
LYS
CD
33.790
56.625
40.936
52.61


97
LYS
CE
34.890
57.651
41.277
51.86


98
LYS
NZ
36.251
57.064
41.269
49.92


99
SER
N
36.087
54.345
38.162
39.93


100
SER
CA
36.820
54.789
37.003
41.11


101
SER
C
37.425
53.593
36.217
41.60


102
SER
O
37.968
53.748
35.149
44.13


103
SER
CB
37.986
55.539
37.561
41.13


104
SER
OG
38.877
54.652
38.356
43.06


105
GLY
N
37.399
52.386
36.767
39.95


106
GLY
CA
38.129
51.274
36.127
36.83


107
GLY
C
39.671
51.290
36.223
35.39


108
GLY
O
40.316
50.783
35.320
37.15


109
SER
N
40.279
51.841
37.301
32.66


110
SER
CA
41.780
51.938
37.308
31.67


111
SER
C
42.598
50.665
37.811
29.26


112
SER
O
43.741
50.778
38.218
28.04


113
SER
CB
42.337
53.166
38.097
32.05


114
SER
OG
41.454
54.345
38.032
36.33


115
TRP
N
42.019
49.485
37.773
26.65


116
TRP
CA
42.787
48.357
38.207
21.95


117
TRP
C
44.128
48.196
37.429
21.43


118
TRP
O
45.199
48.050
38.019
21.86


119
TRP
CB
41.882
47.101
38.149
22.70


120
TRP
CG
40.932
47.148
39.318
20.91


121
TRP
CD1
39.592
47.426
39.181
21.20


122
TRP
CD2
41.184
47.089
40.757
21.02


123
TRP
NE1
39.031
47.559
40.408
21.97


124
TRP
CE2
39.970
47.310
41.388
20.57


125
TRP
CE3
42.283
46.789
41.551
18.68


126
TRP
CZ2
39.847
47.294
42.770
20.86


127
TRP
CZ3
42.185
46.754
42.958
16.67


128
TRP
CH2
40.956
46.981
43.559
19.85


129
ALA
N
44.103
48.273
36.096
21.75


130
ALA
CA
45.413
48.072
35.405
21.29


131
ALA
C
46.515
49.117
35.696
19.48


132
ALA
O
47.664
48.776
35.736
17.73


133
ALA
CB
45.192
47.958
33.915
21.57


134
ALA
N
46.103
50.326
35.925
21.34


135
ALA
CA
46.952
51.428
36.319
20.36


136
ALA
C
47.471
51.300
37.816
20.18


137
ALA
O
48.633
51.406
38.160
23.47


138
ALA
CB
45.932
52.549
36.136
21.69


139
ILE
N
46.537
50.973
38.753
20.36


140
ILE
CA
47.001
50.649
40.115
20.21


141
ILE
C
48.074
49.511
40.105
19.21


142
ILE
O
49.155
49.583
40.676
20.20


143
ILE
CB
45.776
50.220
40.970
21.58


144
ILE
CG1
44.697
51.339
41.220
25.33


145
ILE
CG2
46.173
49.573
42.320
23.50


146
ILE
CD1
45.051
52.433
42.267
26.28


147
TYR
N
47.688
48.424
39.421
18.90


148
TYR
CA
48.574
47.264
39.255
16.59


149
TYR
C
49.878
47.625
38.498
19.69


150
TYR
O
50.967
47.421
38.997
21.05


151
TYR
CB
47.748
46.176
38.592
15.48


152
TYR
CG
48.537
44.932
38.537
15.58


153
TYR
CD1
48.907
44.209
39.665
15.71


154
TYR
CD2
48.960
44.470
37.316
17.07


155
TYR
CE1
49.695
43.057
39.598
15.33


156
TYR
CE2
49.775
43.341
37.218
18.24


157
TYR
CZ
50.173
42.628
38.344
17.83


158
TYR
OH
50.982
41.544
38.105
16.43


159
GLN
N
49.759
48.251
37.330
20.71


160
GLN
CA
50.882
48.930
36.627
23.54


161
GLN
C
51.839
49.705
37.616
21.33


162
GLN
O
53.047
49.495
37.568
22.52


163
GLN
CB
50.268
49.816
35.499
29.74


164
GLN
CG
49.671
49.057
34.238
43.77


165
GLN
CD
48.539
49.650
33.267
50.76


166
GLN
OE1
47.671
50.472
33.495
53.37


167
GLN
NE2
48.508
49.076
32.066
51.41


168
ASP
N
51.244
50.451
38.587
22.69


169
ASP
CA
51.903
51.194
39.649
23.75


170
ASP
C
52.715
50.305
40.609
21.78


171
ASP
O
53.932
50.387
40.718
21.26


172
ASP
CB
50.890
52.087
40.353
26.73


173
ASP
CG
50.646
53.429
39.655
31.02


174
ASP
OD1
51.574
53.975
39.025
31.00


175
ASP
OD2
49.544
53.975
39.841
32.48


176
ILE
N
52.020
49.333
41.202
20.63


177
ILE
CA
52.741
48.290
41.962
19.38


178
ILE
C
53.874
47.578
41.116
19.66


179
ILE
O
54.989
47.370
41.576
18.07


180
ILE
CB
51.688
47.279
42.579
19.75


181
ILE
CG1
50.762
48.016
43.509
19.61


182
ILE
CG2
52.236
46.021
43.304
16.65


183
ILE
CD1
49.363
47.437
43.437
21.44


184
ARG
N
53.565
47.169
39.884
19.64


185
ARG
CA
54.567
46.484
39.085
22.20


186
ARG
C
55.816
47.437
39.067
22.74


187
ARG
O
56.932
46.979
39.099
20.20


188
ARG
CB
54.023
46.237
37.637
23.80


189
ARG
CG
53.320
44.918
37.290
29.28


190
ARG
CD
53.204
44.519
35.775
38.17


191
ARG
NE
52.689
43.130
35.686
47.71


192
ARG
CZ
53.098
42.163
34.783
46.22


193
ARG
NH1
53.704
42.464
33.629
51.10


194
ARG
NH2
52.965
40.881
35.132
39.82


195
HIS
N
55.615
48.784
39.064
24.89


196
HIS
CA
56.730
49.740
38.862
28.65


197
HIS
C
57.493
50.276
40.108
27.86


198
HIS
O
58.673
50.654
40.038
29.52


199
HIS
CB
56.179
50.983
38.193
36.09


200
HIS
CG
56.811
51.114
36.834
47.89


201
HIS
ND1
58.149
50.961
36.592
52.16


202
HIS
CD2
56.145
51.425
35.625
50.80


203
HIS
CE1
58.303
51.179
35.262
54.85


204
HIS
NE2
57.113
51.465
34.656
55.16


205
GLU
N
56.716
50.341
41.204
24.60


206
GLU
CA
57.222
50.671
42.538
23.35


207
GLU
C
57.907
49.520
43.236
20.84


208
GLU
O
58.770
49.755
44.059
20.77


209
GLU
CB
56.078
51.097
43.441
25.78


210
GLU
CG
55.482
52.418
43.015
34.71


211
GLU
CD
54.294
52.679
43.916
41.97


212
GLU
OE1
54.457
52.660
45.153
47.08


213
GLU
OE2
53.218
52.905
43.375
42.03


214
ALA
N
57.458
48.299
42.919
20.22


215
ALA
CA
58.071
47.145
43.572
18.85


216
ALA
C
59.618
47.108
43.413
19.60


217
ALA
O
60.137
47.773
42.539
21.31


218
ALA
CB
57.514
45.879
42.928
17.65


219
SER
N
60.263
46.351
44.323
17.44


220
SER
CA
61.700
46.463
44.627
17.65


221
SER
C
62.475
45.590
43.693
20.44


222
SER
O
61.875
44.737
43.028
20.82


223
SER
CB
61.987
45.892
46.086
16.87


224
SER
OG
60.908
46.087
47.088
17.03


225
ASP
N
63.806
45.769
43.757
23.65


226
ASP
CA
64.608
44.993
42.881
25.32


227
ASP
C
65.953
44.653
43.545
24.00


228
ASP
O
66.834
45.495
43.638
25.47


229
ASP
CB
64.577
45.897
41.647
30.03


230
ASP
CG
65.409
45.356
40.505
35.94


231
ASP
OD1
65.782
44.168
40.576
37.82


232
ASP
OD2
65.652
46.122
39.542
40.50


233
PHE
N
66.128
43.392
44.016
20.26


234
PHE
CA
67.429
43.035
44.653
17.74


235
PHE
C
68.199
42.026
43.725
19.63


236
PHE
O
67.571
41.347
42.920
18.88


237
PHE
CB
67.148
42.482
46.088
15.74


238
PHE
CG
66.400
43.443
47.024
14.99


239
PHE
CD1
67.009
44.602
47.475
14.29


240
PHE
CD2
65.081
43.181
47.458
11.07


241
PHE
CE1
66.294
45.491
48.252
13.28


242
PHE
CE2
64.379
44.048
48.267
12.04


243
PHE
CZ
64.998
45.216
48.653
14.86


244
PRO
N
69.545
41.908
43.722
19.03


245
PRO
CA
70.154
40.759
43.057
17.74


246
PRO
C
69.576
39.346
43.319
17.59


247
PRO
O
69.475
38.926
44.441
18.11


248
PRO
CB
71.601
40.765
43.541
17.29


249
PRO
CG
71.547
41.671
44.730
17.67


250
PRO
CD
70.462
42.691
44.470
17.97


251
CYS
N
69.285
38.589
42.224
16.91


252
CYS
CA
69.204
37.088
42.281
16.83


253
CYS
C
70.495
36.319
41.751
17.10


254
CYS
O
70.417
35.519
40.790
15.98


255
CYS
CB
68.007
36.580
41.502
17.42


256
CYS
SG
66.580
37.626
41.691
21.76


257
ARG
N
71.667
36.666
42.348
17.15


258
ARG
CA
72.970
36.242
41.791
19.32


259
ARG
C
73.119
34.699
41.788
19.49


260
ARG
O
73.496
34.047
40.814
19.32


261
ARG
CB
74.079
36.850
42.622
24.18


262
ARG
CG
74.980
37.833
41.912
34.75


263
ARG
CD
75.311
39.152
42.663
42.80


264
ARG
NE
75.471
39.097
44.113
51.13


265
ARG
CZ
74.828
39.887
45.009
51.47


266
ARG
NH1
74.701
41.151
44.646
48.86


267
ARG
NH2
74.350
39.441
46.136
48.27


268
VAL
N
72.830
34.041
42.924
17.97


269
VAL
CA
72.998
32.576
42.948
16.80


270
VAL
C
71.992
31.806
41.998
15.05


271
VAL
O
72.306
30.779
41.377
15.45


272
VAL
CB
73.273
32.034
44.312
18.01


273
VAL
CG1
72.573
30.756
44.520
15.99


274
VAL
CG2
72.876
32.942
45.388
17.07


275
ALA
N
70.819
32.430
41.831
14.53


276
ALA
CA
69.795
31.819
41.038
14.43


277
ALA
C
70.213
31.697
39.659
15.46


278
ALA
O
69.747
30.800
38.995
16.10


279
ALA
CB
68.535
32.680
41.126
12.61


280
LYS
N
71.076
32.655
39.323
17.52


281
LYS
CA
71.665
32.762
37.982
17.70


282
LYS
C
72.998
32.019
37.847
19.60


283
LYS
O
73.580
32.004
36.776
22.60


284
LYS
CB
71.858
34.261
37.582
19.24


285
LYS
CG
70.573
35.200
37.622
19.97


286
LYS
CD
69.498
34.765
36.639
21.69


287
LYS
CE
68.278
35.680
36.497
24.74


288
LYS
NZ
67.268
34.860
35.757
26.46


289
LEU
N
73.581
31.431
38.936
20.39


290
LEU
CA
74.928
30.843
38.665
19.13


291
LEU
C
74.792
29.677
37.700
21.96


292
LEU
O
73.908
28.875
37.880
20.82


293
LEU
CB
75.585
30.242
39.923
18.89


294
LEU
CG
75.924
31.268
40.972
17.87


295
LEU
CD1
76.848
32.313
40.400
19.14


296
LEU
CD2
76.506
30.672
42.266
17.39


297
PRO
N
75.721
29.419
36.742
23.61


298
PRO
CA
75.299
28.411
35.767
24.44


299
PRO
C
75.014
27.017
36.391
22.23


300
PRO
O
74.374
26.171
35.790
23.82


301
PRO
CB
76.375
28.491
34.687
26.16


302
PRO
CG
76.896
29.926
34.822
27.75


303
PRO
CD
76.869
30.196
36.324
26.72


304
LYS
N
75.512
26.800
37.638
22.30


305
LYS
CA
75.166
25.529
38.233
22.26


306
LYS
C
73.654
25.317
38.489
22.91


307
LYS
O
73.187
24.168
38.569
25.95


308
LYS
CB
76.067
25.121
39.358
23.13


309
LYS
CG
75.991
25.832
40.660
24.19


310
LYS
CD
76.895
25.038
41.664
27.45


311
LYS
CE
77.506
25.823
42.852
31.65


312
LYS
NZ
77.983
24.871
43.905
37.10


313
ASN
N
72.908
26.422
38.604
20.49


314
ASN
CA
71.547
26.288
39.034
18.95


315
ASN
C
70.578
26.384
37.886
19.83


316
ASN
O
69.364
26.402
38.110
16.61


317
ASN
CB
71.326
27.301
40.083
15.32


318
ASN
CG
72.319
27.082
41.210
18.08


319
ASN
OD1
72.774
25.998
41.593
16.89


320
ASN
ND2
72.630
28.223
41.762
17.04


321
LYS
N
71.115
26.261
36.653
19.50


322
LYS
CA
70.198
26.533
35.517
20.65


323
LYS
C
68.970
25.582
35.499
17.99


324
LYS
O
67.827
25.897
35.252
17.79


325
LYS
CB
71.102
26.415
34.280
24.77


326
LYS
CG
70.705
27.324
33.113
35.23


327
LYS
CD
71.780
27.296
31.993
43.17


328
LYS
CE
71.506
28.319
30.877
48.79


329
LYS
NZ
72.095
27.908
29.585
51.89


330
ASN
N
69.249
24.336
35.828
16.87


331
ASN
CA
68.139
23.356
35.844
17.37


332
ASN
C
67.428
23.162
37.209
14.52


333
ASN
O
67.042
22.047
37.553
14.87


334
ASN
CB
68.758
22.008
35.522
17.56


335
ASN
CG
69.723
21.326
36.476
21.16


336
ASN
OD1
70.099
21.716
37.568
23.28


337
ASN
ND2
70.132
20.210
35.940
22.37


338
ARG
N
67.435
24.272
37.960
13.45


339
ARG
CA
66.851
24.363
39.265
14.08


340
ARG
C
65.834
25.455
39.226
11.72


341
ARG
O
64.908
25.455
39.985
11.90


342
ARG
CB
67.927
24.635
40.349
14.72


343
ARG
CG
68.808
23.399
40.637
15.03


344
ARG
CD
69.531
23.566
41.958
13.22


345
ARG
NE
70.329
22.382
42.127
14.96


346
ARG
CZ
70.786
22.027
43.336
15.87


347
ARG
NH1
70.387
22.635
44.429
14.76


348
ARG
NH2
71.629
21.021
43.409
16.81


349
ASN
N
65.990
26.376
38.305
12.70


350
ASN
CA
64.823
27.286
38.125
12.44


351
ASN
C
63.866
26.703
37.067
12.58


352
ASN
O
64.316
26.017
36.196
11.79


353
ASN
CB
65.333
28.584
37.553
15.34


354
ASN
CG
66.254
29.036
38.579
15.14


355
ASN
OD1
65.853
29.008
39.721
13.40


356
ASN
ND2
67.478
29.375
38.192
15.01


357
ARG
N
62.602
26.959
37.101
11.31


358
ARG
CA
61.750
26.422
36.097
10.21


359
ARG
C
61.344
27.550
35.032
11.77


360
ARG
O
60.942
27.244
33.909
10.43


361
ARG
CB
60.569
25.882
36.926
10.53


362
ARG
CG
59.435
25.507
35.982
9.14


363
ARG
CD
58.083
25.567
36.545
10.01


364
ARG
NE
57.805
24.437
37.372
10.47


365
ARG
CZ
57.604
23.255
36.784
10.78


366
ARG
NH1
57.345
22.981
35.539
11.53


367
ARG
NH2
57.847
22.305
37.582
10.00


368
TYR
N
61.531
28.839
35.419
12.06


369
TYR
CA
61.406
29.958
34.471
10.98


370
TYR
C
62.644
30.880
34.512
13.59


371
TYR
O
63.313
31.085
35.519
15.53


372
TYR
CB
60.188
30.734
34.879
9.94


373
TYR
CG
58.902
29.947
34.781
11.54


374
TYR
CD1
58.528
29.222
33.627
11.75


375
TYR
CD2
58.104
29.917
35.903
10.70


376
TYR
CE1
57.373
28.429
33.600
12.58


377
TYR
CE2
56.968
29.113
35.885
11.42


378
TYR
CZ
56.577
28.348
34.738
12.61


379
TYR
OH
55.482
27.467
34.686
13.20


380
ARG
N
63.021
31.367
33.315
13.40


381
ARG
CA
64.268
32.148
33.315
16.28


382
ARG
C
63.947
33.436
34.160
14.00


383
ARG
O
64.804
34.093
34.720
16.44


384
ARG
CB
64.600
32.319
31.810
17.48


385
ARG
CG
65.513
33.475
31.434
23.38


386
ARG
CD
65.168
34.185
30.101
28.56


387
ARG
NE
63.860
34.904
30.168
32.94


388
ARG
CZ
63.004
34.975
29.117
34.20


389
ARG
NH1
63.482
34.836
27.908
33.58


390
ARG
NH2
61.715
35.089
29.282
33.15


391
ASP
N
62.671
33.824
34.184
12.94


392
ASP
CA
62.305
35.149
34.663
12.52


393
ASP
C
61.714
35.183
36.027
12.63


394
ASP
O
61.194
36.232
36.433
11.75


395
ASP
CB
61.233
35.719
33.744
13.44


396
ASP
CG
61.768
36.276
32.470
15.48


397
ASP
OD1
62.985
36.503
32.404
14.91


398
ASP
OD2
60.953
36.507
31.556
17.68


399
VAL
N
61.838
34.020
36.724
12.12


400
VAL
CA
61.386
33.871
38.121
11.29


401
VAL
C
62.363
33.150
39.073
9.78


402
VAL
O
62.300
31.998
39.482
11.48


403
VAL
CB
59.862
33.736
38.326
16.11


404
VAL
CG1
59.564
33.071
39.708
15.44


405
VAL
CG2
59.003
33.367
37.026
14.33


406
SER
N
63.292
34.043
39.508
10.16


407
SER
CA
64.351
33.658
40.430
11.16


408
SER
C
64.044
34.235
41.838
9.64


409
SER
O
63.282
35.201
41.980
11.51


410
SER
CB
65.674
34.207
39.868
10.81


411
SER
OG
65.795
34.206
38.393
12.18


412
PRO
N
64.652
33.603
42.890
8.67


413
PRO
CA
64.679
34.069
44.300
10.79


414
PRO
C
65.739
35.174
44.607
13.35


415
PRO
O
66.863
35.054
44.167
14.81


416
PRO
CB
65.070
32.742
45.027
10.00


417
PRO
CG
65.954
31.994
44.070
10.77


418
PRO
CD
65.350
32.343
42.713
9.16


419
PHE
N
65.333
36.312
45.288
13.59


420
PHE
CA
66.396
37.309
45.592
12.71


421
PHE
C
67.463
36.637
46.469
12.31


422
PHE
O
67.099
35.793
47.313
12.68


423
PHE
CB
65.827
38.538
46.324
9.81


424
PHE
CG
64.721
39.284
45.705
10.06


425
PHE
CD1
64.796
39.648
44.360
9.58


426
PHE
CD2
63.667
39.689
46.481
9.41


427
PHE
CE1
63.839
40.478
43.828
10.26


428
PHE
CE2
62.712
40.531
45.935
10.02


429
PHE
CZ
62.810
40.954
44.617
8.64


430
ASP
N
68.731
37.039
46.301
11.62


431
ASP
CA
69.699
36.442
47.229
12.07


432
ASP
C
69.336
36.779
48.740
12.27


433
ASP
O
69.471
35.939
49.614
15.21


434
ASP
CB
71.090
36.960
46.918
13.40


435
ASP
CG
71.585
36.819
45.512
14.25


436
ASP
OD1
71.510
35.755
45.001
15.72


437
ASP
OD2
72.114
37.776
44.954
12.79


438
HIS
N
68.891
37.987
49.110
12.16


439
HIS
CA
68.936
38.332
50.537
12.71


440
HIS
C
68.037
37.415
51.373
13.92


441
HIS
O
68.357
37.023
52.468
15.61


442
HIS
CB
68.619
39.807
50.639
12.05


443
HIS
CG
67.189
40.229
50.532
10.80


444
HIS
ND1
66.218
40.158
51.532
11.89


445
HIS
CD2
66.595
40.810
49.442
10.89


446
HIS
CE1
65.078
40.670
51.055
9.38


447
HIS
NE2
65.292
41.065
49.801
11.30


448
SER
N
66.911
37.032
50.727
13.43


449
SER
CA
65.732
36.268
51.219
12.13


450
SER
C
65.616
34.786
50.742
12.76


451
SER
O
64.852
33.988
51.280
13.37


452
SER
CB
64.459
36.969
50.655
10.16


453
SER
CG
64.073
36.712
49.237
10.34


454
ARG
N
66.289
34.396
49.662
11.78


455
ARG
CA
66.110
33.011
49.184
13.97


456
ARG
C
66.308
32.030
50.330
13.85


457
ARG
O
67.052
32.388
51.228
11.86


458
ARG
CB
67.182
32.758
48.072
12.96


459
ARG
CG
68.663
32.686
48.534
13.81


460
ARG
CD
69.587
31.920
47.602
13.20


461
ARG
NE
70.951
31.816
48.184
14.78


462
ARG
CZ
71.552
30.688
48.524
15.00


463
ARG
NH1
70.936
29.557
48.478
11.82


464
ARG
NH2
72.784
30.639
48.884
17.64


465
ILE
N
65.654
30.828
50.300
14.21


466
ILE
CA
65.948
29.645
51.217
12.58


467
ILE
C
67.155
28.748
50.720
14.61


468
ILE
O
67.216
28.241
49.587
15.26


469
ILE
CB
64.722
28.774
51.313
13.58


470
ILE
CG1
63.510
29.500
51.879
13.29


471
ILE
CG2
64.977
27.447
52.006
13.64


472
ILE
OD1
63.571
29.924
53.338
13.30


473
LYS
N
68.150
28.621
51.612
15.82


474
LYS
CA
69.276
27.764
51.318
15.98


475
LYS
C
69.096
26.360
51.954
17.60


476
LYS
O
68.984
26.265
53.135
19.95


477
LYS
CB
70.448
28.373
52.073
17.28


478
LYS
CG
70.639
29.851
51.912
17.24


479
LYS
CD
72.028
30.137
52.423
22.81


480
LYS
CE
72.374
31.627
52.475
26.05


481
LYS
NZ
73.787
31.719
52.904
31.86


482
LEU
N
69.186
25.284
51.179
17.25


483
LEU
CA
69.191
23.986
51.803
18.29


484
LEU
C
70.420
23.813
52.707
20.34


485
LEU
O
71.463
24.451
52.542
19.70


486
LEU
CB
69.326
23.009
50.654
18.28


487
LEU
CG
68.077
22.606
49.875
18.66


488
LEU
CD1
68.503
22.354
48.425
17.13


489
LEU
CD2
66.905
23.584
50.003
14.98


490
HIS
N
70.327
22.853
53.607
22.86


491
HIS
CA
71.473
22.568
54.469
25.86


492
HIS
C
72.376
21.544
53.818
30.06


493
HIS
O
72.823
20.636
54.478
31.82


494
HIS
CB
71.011
22.101
55.889
26.12


495
HIS
CG
70.169
23.121
56.652
25.12


496
HIS
ND1
69.669
22.796
57.857
25.76


497
HIS
CD2
69.771
24.443
56.370
24.91


498
HIS
CE1
68.999
23.876
58.293
25.52


499
HIS
NE2
69.054
24.883
57.439
26.33


500
GLN
N
72.654
21.694
52.528
32.94


501
GLN
CA
73.476
20.669
51.845
36.50


502
GLN
C
74.845
21.250
51.490
37.97


503
GLN
O
74.997
22.462
51.350
37.18


504
GLN
CB
72.785
19.969
50.653
37.95


505
GLN
CG
72.220
20.893
49.533
40.06


506
GLN
CD
71.786
20.148
48.187
44.06


507
GLN
OE1
72.396
20.225
47.103
46.49


508
GLN
NE2
70.689
19.404
48.371
41.49


509
GLU
N
75.833
20.321
51.371
41.15


510
GLU
CA
77.175
20.785
50.982
41.70


511
GLU
C
77.356
20.946
49.420
39.31


512
GLU
O
78.061
21.828
48.944
38.68


513
GLU
CB
78.182
19.780
51.511
45.57


514
GLU
CG
78.185
19.584
53.033
54.22


515
GLU
CD
78.719
18.188
53.518
60.23


516
GLU
OE1
79.014
17.293
52.706
63.36


517
GLU
OE2
78.813
18.019
54.741
62.48


518
ASP
N
76.708
20.105
48.601
38.53


519
ASP
CA
77.055
20.312
47.192
37.73


520
ASP
C
76.579
21.706
46.692
33.50


521
ASP
O
77.309
22.594
46.250
35.46


522
ASP
CB
76.361
19.144
46.491
43.21


523
ASP
CG
76.711
19.135
45.008
49.96


524
ASP
OD1
77.838
19.533
44.702
53.55


525
ASP
OD2
75.843
18.784
44.184
52.89


526
ASN
N
75.262
21.863
46.853
28.37


527
ASN
CA
74.553
23.027
46.358
21.99


528
ASN
C
73.354
23.441
47.299
20.24


529
ASN
O
72.312
22.805
47.353
21.87


530
ASN
CB
74.099
22.536
44.960
19.04


531
ASN
CG
73.717
23.704
44.039
18.04


532
ASN
OD1
73.456
24.765
44.530
19.25


533
ASN
ND2
73.728
23.588
42.734
15.06


534
ASP
N
73.466
24.546
48.022
18.00


535
ASP
CA
72.332
25.033
48.836
18.78


536
ASP
C
71.151
25.681
48.030
17.35


537
ASP
O
70.225
26.206
48.623
18.81


538
ASP
CB
72.886
26.063
49.861
19.48


539
ASP
CG
73.288
27.453
49.333
23.10


540
ASP
OD1
72.887
27.851
48.256
24.35


541
ASP
OD2
73.983
28.207
50.021
29.58


542
TYR
N
71.212
25.740
46.675
16.55


543
TYR
CA
70.199
26.452
45.895
12.98


544
TYR
C
68.875
25.687
45.783
12.27


545
TYR
O
68.835
24.576
45.292
12.81


546
TYR
CB
70.772
26.662
44.525
10.36


547
TYR
CG
69.834
27.547
43.751
12.42


548
TYR
CD1
69.670
28.900
44.065
10.55


549
TYR
CD2
69.026
27.003
42.736
11.80


550
TYR
CE1
68.666
29.636
43.411
11.79


551
TYR
CE2
68.002
27.711
42.094
10.71


552
TYR
CZ
67.821
29.072
42.453
9.67


553
TYR
OH
66.838
29.931
41.987
10.99


554
ILE
N
67.843
26.362
46.233
13.06


555
ILE
CA
66.470
26.037
45.852
12.41


556
ILE
C
65.728
27.348
45.344
11.32


557
ILE
O
66.023
28.445
45.836
12.19


558
ILE
CB
65.643
25.321
46.943
12.98


559
ILE
CG1
64.216
25.028
46.401
8.76


560
ILE
CG2
65.631
26.109
48.238
10.91


561
ILE
CD1
63.534
23.768
46.941
9.88


562
ASN
N
64.802
27.274
44.373
9.16


563
ASN
CA
63.961
28.432
44.113
9.65


564
ASN
C
62.777
28.477
45.134
10.37


565
ASN
O
61.669
28.001
44.902
10.07


566
ASN
CB
63.409
28.368
42.689
9.08


567
ASN
CG
62.854
29.669
42.094
9.54


568
ASN
OD1
62.064
30.411
42.717
10.96


569
ASN
ND2
63.215
29.836
40.823
9.06


570
ALA
N
63.053
29.245
46.232
9.41


571
ALA
CA
62.074
29.518
47.285
10.05


572
ALA
C
62.490
30.729
48.081
11.58


573
ALA
O
63.684
31.012
48.161
12.92


574
ALA
CB
62.248
28.369
48.268
7.50


575
SER
N
61.501
31.398
48.688
10.51


576
SER
CA
61.767
32.622
49.448
11.23


577
SER
C
60.986
32.733
50.725
10.85


578
SER
O
59.810
32.408
50.715
12.48


579
SER
CB
61.240
33.808
48.570
7.55


580
SER
OG
61.832
33.943
47.206
10.45


581
LEU
N
61.665
33.227
51.759
11.48


582
LEU
CA
61.028
33.484
53.026
12.53


583
LEU
C
60.459
34.863
52.839
13.15


584
LEU
O
61.162
35.810
52.745
13.65


585
LEU
CB
62.100
33.317
54.125
13.18


586
LEU
CG
61.714
33.026
55.617
15.58


587
LEU
CD1
60.346
32.465
56.032
15.45


588
LEU
CD2
61.990
34.242
56.446
15.90


589
ILE
N
59.142
34.963
52.710
12.91


590
ILE
CA
58.433
36.244
52.854
13.87


591
ILE
C
58.199
36.410
54.383
16.47


592
ILE
O
57.520
35.626
55.029
16.73


593
ILE
CB
57.078
36.103
52.126
13.55


594
ILE
CG1
57.058
36.090
50.580
12.82


595
ILE
CG2
56.084
37.173
52.640
16.67


596
ILE
CD1
58.184
35.285
49.937
12.75


597
LYS
N
58.754
37.425
54.954
16.38


598
LYS
CA
58.733
37.584
56.393
19.03


599
LYS
C
57.916
38.848
56.792
18.79


600
LYS
O
58.361
39.997
56.871
18.39


601
LYS
CB
60.193
37.663
56.758
24.89


602
LYS
CG
60.382
37.380
58.215
36.70


603
LYS
CD
61.837
37.012
58.412
45.35


604
LYS
CE
62.107
36.507
59.815
49.89


605
LYS
NZ
63.542
36.156
59.861
53.29


606
MET
N
56.632
38.598
57.069
17.44


607
MET
CA
55.789
39.713
57.508
17.07


608
MET
C
56.013
39.963
59.034
17.04


609
MET
O
55.491
39.236
59.879
16.87


610
MET
CB
54.344
39.363
57.116
15.46


611
MET
CG
54.239
38.984
55.611
15.47


612
MET
SD
55.075
40.191
54.531
16.71


613
MET
CE
53.670
41.304
54.490
12.89


614
GLU
N
56.792
41.029
59.352
20.27


615
GLU
CA
57.059
41.404
60.754
22.54


616
GLU
C
55.827
42.015
61.552
22.33


617
GLU
O
55.304
41.421
62.490
24.08


618
GLU
CB
58.262
42.322
60.762
26.36


619
GLU
CG
58.891
42.457
62.173
35.25


620
GLU
CD
59.916
43.590
62.166
40.00


621
GLU
OE1
59.477
44.700
61.830
43.15


622
GLU
OE2
61.096
43.345
62.480
43.54


623
GLU
N
55.283
43.165
61.103
23.41


624
GLU
CA
54.028
43.623
61.715
24.81


625
GLU
C
52.959
42.499
61.936
24.74


626
GLU
O
52.437
42.295
63.015
24.77


627
GLU
CB
53.482
44.704
60.837
26.99


628
GLU
CG
52.576
45.679
61.608
35.79


629
GLU
CD
51.974
46.718
60.634
45.06


630
GLU
OE1
52.430
46.765
59.511
48.32


631
GLU
OE2
51.091
47.475
61.022
49.68


632
ALA
N
52.665
41.750
60.868
22.17


633
ALA
CA
51.673
40.706
60.947
21.64


634
ALA
C
52.213
39.523
61.660
22.46


635
ALA
O
51.470
38.690
62.105
24.05


636
ALA
CB
51.310
40.191
59.565
20.53


637
GLN
N
53.508
39.446
61.797
23.74


638
GLN
CA
53.951
38.375
62.649
27.80


639
GLN
C
53.494
36.942
62.164
26.92


640
GLN
O
53.212
36.073
62.988
27.71


641
GLN
CB
53.604
38.695
64.142
32.88


642
GLN
CG
54.557
39.626
64.990
40.36


643
GLN
CD
55.637
38.789
65.755
47.19


644
GLN
OE1
55.413
38.194
66.807
52.84


645
GLN
NE2
56.809
38.690
65.144
46.59


646
ARG
N
53.576
36.814
60.781
23.43


647
ARG
CA
53.512
35.548
59.983
18.91


648
ARG
C
54.532
35.508
58.799
16.84


649
ARG
O
54.660
36.485
58.081
17.96


650
ARG
CB
52.108
35.410
59.417
18.58


651
ARG
CG
51.983
33.974
58.874
16.36


652
ARG
CD
50.561
33.599
58.555
17.70


653
ARG
NE
49.917
33.327
59.836
17.29


654
ARG
CZ
48.629
33.215
59.998
15.94


655
ARG
NH1
47.869
33.433
58.973
13.68


656
ARG
NH2
48.184
32.917
61.156
18.40


657
SER
N
55.331
34.440
58.582
13.82


658
SER
CA
56.164
34.277
57.366
12.48


659
SER
C
55.588
33.151
56.471
11.37


660
SER
O
54.899
32.287
56.921
13.16


661
SER
CB
57.601
33.787
57.603
12.86


662
SER
OG
58.317
33.977
58.878
19.01


663
TYR
N
56.004
33.108
55.215
11.99


664
TYR
CA
55.704
31.895
54.458
10.12


665
TYR
C
56.953
31.593
53.701
10.62


666
TYR
O
57.730
32.497
53.459
11.32


667
TYR
CB
54.616
32.184
53.384
10.39


668
TYR
CG
53.469
33.063
53.849
10.08


669
TYR
CD1
53.696
34.400
54.011
10.55


670
TYR
CD2
52.208
32.580
54.154
10.53


671
TYR
CE1
52.769
35.233
54.522
12.90


672
TYR
CE2
51.239
33.420
54.642
12.10


673
TYR
CZ
51.530
34.723
54.834
13.13


674
TYR
OH
50.524
35.465
55.346
13.22


675
ILE
N
57.104
30.369
53.235
10.35


676
ILE
CA
58.077
30.153
52.147
7.97


677
ILE
C
57.178
30.151
50.851
9.78


678
ILE
O
56.263
29.348
50.833
10.25


679
ILE
CB
58.953
28.883
52.458
9.05


680
ILE
CG1
59.740
29.088
53.740
10.20


681
ILE
CG2
59.957
28.496
51.397
8.37


682
ILE
CD1
60.474
27.819
54.246
8.33


683
LEU
N
57.403
31.084
49.833
8.73


684
LEU
CA
56.855
30.922
48.465
8.66


685
LEU
C
57.905
30.236
47.526
11.10


686
LEU
O
59.110
30.576
47.552
12.49


687
LEU
CB
56.561
32.244
47.860
9.65


688
LEU
CG
55.257
32.826
48.326
10.58


689
LEU
CD1
54.913
34.147
47.565
11.19


690
LEU
CD2
55.270
32.940
49.838
12.47


691
THR
N
57.402
29.203
46.761
10.83


692
THR
CA
58.299
28.363
45.895
8.06


693
THR
C
57.668
28.097
44.482
9.10


694
THR
O
56.489
28.380
44.264
8.53


695
THR
CB
58.859
27.100
46.647
8.87


696
THR
OG1
59.976
26.366
45.972
11.27


697
THR
CG2
57.803
26.211
47.344
8.63


698
GLN
N
58.506
27.610
43.519
7.55


699
GLN
CA
57.990
27.172
42.176
7.51


700
GLN
C
57.437
25.750
42.219
8.15


701
GLN
O
57.723
24.997
43.143
9.26


702
GLN
CB
59.060
27.244
41.087
7.72


703
GLN
CG
60.130
26.188
41.317
7.48


704
GLN
CD
61.257
26.336
40.384
7.54


705
GLN
OE1
61.977
25.398
40.166
13.65


706
GLN
NE2
61.511
27.505
39.888
6.16


707
GLY
N
56.603
25.377
41.221
8.70


708
GLY
CA
56.238
23.982
41.272
8.95


709
GLY
C
57.520
23.130
41.108
10.89


710
GLY
O
58.254
23.333
40.156
12.56


711
PRO
N
57.762
22.179
42.005
11.90


712
PRO
CA
58.999
21.445
41.898
10.45


713
PRO
C
59.179
20.901
40.444
12.59


714
PRO
O
58.192
20.592
39.776
12.30


715
PRO
CB
58.889
20.400
42.984
10.51


716
PRO
CG
57.757
20.889
43.873
11.89


717
PRO
CD
56.917
21.895
43.147
9.07


718
LEU
N
60.423
20.963
39.954
13.19


719
LEU
CA
60.928
20.422
38.711
14.02


720
LEU
C
61.288
18.972
38.994
13.93


721
LEU
O
61.401
18.617
40.157
12.95


722
LEU
CB
62.178
21.303
38.472
13.39


723
LEU
CG
62.181
22.123
37.185
14.69


724
LEU
CD1
62.862
23.432
37.390
13.28


725
LEU
CD2
60.808
22.403
36.589
12.21


726
PRO
N
61.492
18.060
38.006
16.81


727
PRO
CA
61.666
16.641
38.394
17.34


728
PRO
C
62.962
16.281
39.104
16.85


729
PRO
O
63.122
15.247
39.688
18.24


730
PRO
CB
61.517
15.864
37.116
17.12


731
PRO
CG
60.922
16.848
36.100
19.47


732
PRO
CD
61.300
18.261
36.556
16.45


733
ASN
N
63.900
17.198
39.011
15.30


734
ASN
CA
65.204
16.949
39.638
14.86


735
ASN
C
65.487
17.673
40.952
15.36


736
ASN
O
66.603
17.703
41.410
15.84


737
ASN
CB
66.197
17.452
38.620
14.48


738
ASN
CG
65.975
18.909
38.203
16.03


739
ASN
OD1
65.058
19.216
37.443
19.68


740
ASN
ND2
66.878
19.774
38.721
15.67


741
THR
N
64.484
18.374
41.425
15.02


742
THR
CA
64.442
19.135
42.712
12.29


743
THR
C
63.211
18.662
43.532
11.96


744
THR
O
62.712
19.350
44.385
11.69


745
THR
CB
64.049
20.608
42.328
10.87


746
THR
OG1
62.724
20.721
41.769
10.92


747
THR
CG2
64.891
21.218
41.196
10.49


748
CYS
N
62.634
17.505
43.321
14.04


749
CYS
CA
61.483
17.193
44.179
14.17


750
CYS
C
62.088
16.768
45.539
12.97


751
CYS
O
61.464
16.855
46.615
13.90


752
CYS
CB
60.644
16.031
43.646
13.16


753
CYS
SG
59.565
16.488
42.264
15.24


754
GLY
N
63.405
16.394
45.404
13.25


755
GLY
CA
64.191
15.974
46.563
14.11


756
GLY
C
64.788
17.158
47.402
14.77


757
GLY
O
64.846
17.059
48.598
15.71


758
HIS
N
65.185
18.303
46.789
15.04


759
HIS
CA
65.415
19.657
47.379
13.49


760
HIS
C
64.101
20.265
47.972
14.38


761
HIS
O
64.083
20.721
49.105
15.19


762
HIS
CB
65.898
20.682
46.344
12.89


763
HIS
CG
67.036
20.181
45.457
14.63


764
HIS
ND1
67.075
20.421
44.117
13.48


765
HIS
CD2
68.117
19.333
45.753
16.55


766
HIS
CE1
68.090
19.729
43.613
14.33


767
HIS
NE2
68.744
19.084
44.580
15.87


768
PHE
N
62.967
20.201
47.261
12.72


769
PHE
CA
61.732
20.613
47.958
12.68


770
PHE
C
61.548
19.898
49.353
13.22


771
PHE
O
61.483
20.497
50.423
12.12


772
PHE
CB
60.586
20.347
46.968
12.82


773
PHE
CG
59.235
20.806
47.480
9.60


774
PHE
CD1
58.367
19.945
48.151
8.18


775
PHE
CD2
58.819
22.104
47.261
8.54


776
PHE
CE1
57.135
20.383
48.629
11.79


777
PHE
CE2
57.551
22.497
47.662
11.03


778
PHE
CZ
56.712
21.647
48.354
10.70


779
TRP
N
61.531
18.566
49.377
12.17


780
TRP
CA
61.277
17.960
50.667
12.15


781
TRP
C
62.426
18.110
51.675
12.77


782
TRP
O
62.267
17.797
52.824
12.89


783
TRP
CB
60.914
16.499
50.457
13.28


784
TRP
CG
59.487
16.421
49.968
13.46


785
TRP
CD1
59.176
16.003
48.715
13.99


786
TRP
CD2
58.238
16.857
50.571
12.69


787
TRP
NE1
57.858
16.174
48.514
13.76


788
TRP
CE2
57.224
16.674
49.611
12.21


789
TRP
CE3
57.892
17.354
51.835
11.54


790
TRP
CZ2
55.928
17.024
49.845
11.49


791
TRP
CZ3
56.569
17.707
52.119
12.46


792
TRP
CH2
55.598
17.545
51.099
11.61


793
GLU
N
63.588
18.588
51.263
13.48


794
GLU
CA
64.731
18.763
52.162
12.78


795
GLU
C
64.458
20.064
52.881
13.54


796
GLU
O
64.488
20.065
54.123
13.56


797
GLU
CB
66.084
18.779
51.401
11.88


798
GLU
CG
67.269
19.356
52.235
15.11


799
GLU
CD
68.554
19.518
51.499
17.43


800
GLU
OE1
68.577
19.290
50.284
19.12


801
GLU
OE2
69.547
19.872
52.101
19.81


802
MET
N
63.973
21.049
51.994
11.71


803
MET
CA
63.546
22.379
52.486
12.23


804
MET
C
62.389
22.312
53.511
11.68


805
MET
O
62.291
22.943
54.555
11.24


806
MET
CB
63.108
23.239
51.328
9.82


807
MET
CG
62.214
24.420
51.724
11.63


808
MET
SD
61.999
25.602
50.392
15.04


809
MET
CE
60.555
24.934
49.564
11.38


810
VAL
N
61.422
21.461
53.168
12.17


811
VAL
CA
60.354
21.227
54.164
10.63


812
VAL
C
60.941
20.624
55.438
13.77


813
VAL
O
60.589
21.011
56.523
14.26


814
VAL
CB
59.220
20.388
53.522
10.58


815
VAL
CG1
58.576
21.226
52.398
8.22


816
VAL
CG2
58.132
19.960
54.487
10.48


817
TRP
N
61.857
19.696
55.332
13.52


818
TRP
CA
62.368
19.071
56.546
14.59


819
TRP
C
63.063
20.108
57.515
15.04


820
TRP
O
62.665
20.298
58.672
16.22


821
TRP
CB
63.263
17.908
56.111
12.97


822
TRP
CG
63.663
17.210
57.352
17.46


823
TRP
CD1
64.811
17.506
58.070
21.61


824
TRP
CD2
62.942
16.235
58.122
19.79


825
TRP
NE1
64.831
16.777
59.222
23.85


826
TRP
CE2
63.721
15.974
59.290
22.70


827
TRP
CE3
61.749
15.593
57.954
21.09


828
TRP
CZ2
63.300
15.074
60.220
21.76


829
TRP
CZ3
61.323
14.679
58.916
21.15


830
TRP
CH2
62.094
14.409
60.031
21.23


831
GLU
N
64.079
20.742
56.935
16.06


832
GLU
CA
65.024
21.609
57.615
15.05


833
GLU
C
64.396
22.880
58.008
16.50


834
GLU
O
64.758
23.461
59.019
18.37


835
GLU
CB
66.099
21.948
56.599
13.43


836
GLU
CG
66.738
20.660
56.125
13.77


837
GLU
CD
67.820
20.935
55.146
14.43


838
GLU
OE1
67.899
22.007
54.586
15.87


839
GLU
OE2
68.632
20.038
54.975
15.61


840
GLN
N
63.390
23.283
57.230
14.99


841
GLN
CA
62.612
24.477
57.635
14.10


842
GLN
C
61.510
24.226
58.676
14.79


843
GLN
O
60.879
25.146
59.160
14.03


844
GLN
CB
62.048
25.170
56.347
13.84


845
GLN
CG
63.212
25.595
55.375
14.77


846
GLN
CD
64.194
26.544
56.098
20.12


847
GLN
OE1
63.694
27.506
56.665
21.85


848
GLN
NE2
65.471
26.331
56.071
18.11


849
LYS
N
61.251
22.954
59.012
14.24


850
LYS
CA
60.227
22.483
59.980
15.01


851
LYS
C
58.797
22.890
59.696
12.96


852
LYS
O
57.994
22.992
60.604
13.31


853
LYS
CB
60.584
22.912
61.402
19.21


854
LYS
CG
62.055
22.609
61.711
21.85


855
LYS
CD
62.235
22.379
63.198
29.47


856
LYS
CE
63.661
22.216
63.640
31.82


857
LYS
NZ
64.341
23.105
62.727
37.86


858
SER
N
58.495
23.079
58.406
14.72


859
SER
CA
57.092
23.282
58.019
14.22


860
SER
C
56.246
22.042
58.300
15.12


861
SER
O
56.655
20.897
58.189
14.48


862
SER
CB
57.124
23.649
56.489
12.78


863
SER
OG
58.109
24.701
56.039
13.54


864
ARG
N
55.046
22.316
58.638
13.87


865
ARG
CA
53.889
21.469
58.787
14.62


866
ARG
C
52.900
21.380
57.558
14.77


867
ARG
O
52.279
20.349
57.295
13.72


868
ARG
CB
53.162
22.084
59.989
14.39


869
ARG
CG
52.448
21.021
60.790
23.02


870
ARG
CD
51.000
20.993
60.443
27.49


871
ARG
NE
50.286
20.242
61.462
30.20


872
ARG
CZ
50.380
18.916
61.522
29.90


873
ARG
NH1
51.307
18.211
60.950
31.36


874
ARG
NH2
49.427
18.304
62.133
30.49


875
GLY
N
52.739
22.450
56.827
15.17


876
GLY
CA
51.776
22.626
55.799
13.10


877
GLY
C
52.462
22.850
54.485
12.93


878
GLY
O
53.449
23.538
54.399
12.18


879
VAL
N
51.894
22.272
53.426
13.38


880
VAL
CA
52.274
22.713
52.082
10.87


881
VAL
C
50.983
23.124
51.461
9.66


882
VAL
O
50.002
22.387
51.541
10.04


883
VAL
CB
52.870
21.528
51.228
10.73


884
VAL
CG1
54.155
20.840
51.773
11.72


885
VAL
CG2
53.136
21.897
49.737
10.72


886
VAL
N
51.007
24.297
50.825
8.51


887
VAL
CA
49.805
24.732
50.087
7.91


888
VAL
C
50.113
24.799
48.608
8.39


889
VAL
O
50.967
25.546
48.186
9.71


890
VAL
CB
49.346
26.112
50.615
6.14


891
VAL
CG1
48.848
26.046
52.098
7.70


892
VAL
CG2
48.214
26.748
49.800
6.32


893
MET
N
49.389
24.005
47.841
8.82


894
MET
CA
49.534
23.899
46.386
8.53


895
MET
C
48.365
24.505
45.638
9.29


896
MET
O
47.289
23.983
45.711
9.66


897
MET
CB
49.534
22.412
46.115
8.63


898
MET
CG
49.584
22.144
44.622
9.02


899
MET
SD
50.458
20.629
44.313
13.59


900
MET
CE
50.211
20.435
42.521
7.30


901
LEU
N
48.591
25.598
44.954
8.05


902
LEU
CA
47.428
26.275
44.340
6.79


903
LEU
C
47.172
26.020
42.785
8.29


904
LEU
O
46.566
26.877
42.182
8.17


905
LEU
CB
47.688
27.800
44.449
8.82


906
LEU
CG
47.991
28.331
45.842
9.33


907
LEU
CD1
46.842
28.070
46.813
6.68


908
LEU
CD2
48.214
29.832
45.771
8.69


909
ASN
N
47.920
25.017
42.200
8.85


910
ASN
CA
48.020
24.702
40.735
10.85


911
ASN
C
47.769
23.175
40.514
10.96


912
ASN
O
48.012
22.421
41.451
11.52


913
ASN
CB
49.393
25.060
40.117
10.56


914
ASN
CG
50.568
24.084
40.487
10.18


915
ASN
OD1
51.127
23.276
39.749
13.30


916
ASN
ND2
51.129
24.353
41.654
6.84


917
ARG
N
47.424
22.750
39.274
12.81


918
ARG
CA
47.423
21.308
38.970
12.84


919
ARG
C
48.776
20.954
38.393
13.06


920
ARG
O
49.452
21.835
37.869
13.72


921
ARG
CB
46.231
20.948
38.085
15.06


922
ARG
CG
44.960
21.740
38.453
23.73


923
ARG
CD
43.614
21.096
38.015
34.40


924
ARG
NE
43.483
20.691
36.595
44.56


925
ARG
CZ
43.334
21.619
35.619
51.42


926
ARG
NH1
43.467
22.892
35.787
54.99


927
ARG
NH2
42.994
21.256
34.403
53.99


928
VAL
N
49.195
19.695
38.452
13.43


929
VAL
CA
50.346
19.256
37.704
16.12


930
VAL
C
50.278
19.565
36.147
16.48


931
VAL
O
51.114
20.226
35.584
14.56


932
VAL
CB
50.559
17.783
38.070
14.79


933
VAL
CG1
50.930
17.661
39.553
14.80


934
VAL
CG2
51.639
17.182
37.160
16.58


935
MET
N
49.229
19.073
35.453
17.62


936
MET
CA
48.799
19.616
34.173
19.41


937
MET
C
47.577
20.606
34.287
17.22


938
MET
O
46.471
20.315
34.733
16.41


939
MET
CB
48.548
18.474
33.180
22.53


940
MET
CG
48.920
18.893
31.711
30.44


941
MET
SD
48.488
17.626
30.498
36.43


942
MET
CE
46.891
18.345
30.183
32.23


943
GLU
N
47.925
21.768
33.762
17.49


944
GLU
CA
47.082
22.928
33.568
18.64


945
GLU
C
47.552
23.550
32.237
17.88


946
GLU
O
48.753
23.611
31.959
18.32


947
GLU
CB
47.409
24.092
34.512
16.54


948
GLU
CG
47.652
23.731
35.929
16.82


949
GLU
CD
47.619
24.979
36.772
15.94


950
GLU
OE1
48.517
25.821
36.630
15.52


951
GLU
OE2
46.727
25.093
37.611
15.98


952
LYS
N
46.605
23.992
31.444
19.17


953
LYS
CA
46.693
24.610
30.148
20.14


954
LYS
C
47.513
23.739
29.202
18.74


955
LYS
O
48.351
24.244
28.449
18.86


956
LYS
CB
47.304
25.984
30.368
21.50


957
LYS
CG
46.267
26.889
31.035
24.11


958
LYS
CD
46.770
28.322
31.089
28.82


959
LYS
CE
45.657
29.354
31.107
30.30


960
LYS
NZ
44.532
28.741
31.820
32.58


961
GLY
N
47.273
22.392
29.319
18.79


962
GLY
CA
47.911
21.493
28.344
17.83


963
GLY
C
49.363
21.124
28.602
19.02


964
GLY
O
49.889
20.163
28.022
18.80


965
SER
N
49.994
21.951
29.434
16.08


966
SER
CA
51.417
21.727
29.690
17.76


967
SER
C
51.563
21.319
31.153
16.07


968
SER
O
50.624
21.508
31.921
15.80


969
SER
CB
52.195
22.984
29.281
21.32


970
SER
OG
51.454
23.745
28.215
29.95


971
LEU
N
52.706
20.665
31.433
16.19


972
LEU
CA
53.044
20.095
32.721
14.22


973
LEU
C
53.814
21.162
33.523
14.90


974
LEU
O
54.937
21.513
33.212
16.30


975
LEU
CB
53.928
18.847
32.505
13.16


976
LEU
CG
53.098
17.636
32.063
12.66


977
LEU
CD1
52.255
17.105
33.249
15.43


978
LEU
CD2
53.993
16.510
31.569
13.88


979
LYS
N
53.070
21.738
34.484
14.30


980
LYS
CA
53.355
22.962
35.234
11.19


981
LYS
C
54.103
22.727
36.555
10.51


982
LYS
O
54.480
23.691
37.202
11.24


983
LYS
CB
51.969
23.563
35.492
11.90


984
LYS
CG
51.377
24.141
34.173
15.22


985
LYS
CD
52.251
25.323
33.894
16.86


986
LYS
CE
51.945
26.341
32.815
20.26


987
LYS
NZ
52.785
27.477
33.270
18.45


988
CYS
N
54.265
21.458
36.919
10.35


989
CYS
CA
54.800
21.085
38.199
10.12


990
CYS
C
55.093
19.570
38.124
13.34


991
CYS
O
54.346
18.872
37.449
13.61


992
CYS
CB
53.752
21.438
39.298
13.04


993
CYS
SG
54.171
21.096
41.056
11.06


994
ALA
N
56.092
19.102
38.912
11.84


995
ALA
CA
56.384
17.664
39.115
11.47


996
ALA
C
55.350
16.986
39.954
13.20


997
ALA
O
54.725
17.565
40.853
10.87


998
ALA
CB
57.698
17.551
39.874
9.90


999
GLN
N
55.227
15.685
39.755
12.25


1000
GLN
CA
54.380
14.965
40.731
13.18


1001
GLN
C
55.285
14.601
41.907
13.71


1002
GLN
O
55.974
13.592
41.922
14.92


1003
GLN
CB
53.719
13.735
40.112
13.64


1004
GLN
CG
52.758
12.973
41.060
14.19


1005
GLN
CD
51.427
13.725
41.216
14.78


1006
GLN
OE1
50.905
13.910
42.309
20.52


1007
GLN
NE2
50.901
14.217
40.086
13.59


1008
TYR
N
55.306
15.502
42.891
12.19


1009
TYR
CA
56.373
15.447
43.967
11.14


1010
TYR
C
55.940
14.903
45.328
10.72


1011
TYR
O
56.779
14.953
46.207
12.61


1012
TYR
CB
56.928
16.825
44.297
10.70


1013
TYR
CG
55.892
17.745
44.873
12.19


1014
TYR
CD1
55.710
17.845
46.233
10.21


1015
TYR
CD2
55.141
18.558
44.050
11.16


1016
TYR
CE1
54.801
18.729
46.793
12.37


1017
TYR
CE2
54.213
19.435
44.555
10.83


1018
TYR
CZ
54.033
19.497
45.943
11.09


1019
TYR
OH
53.050
20.302
46.488
11.70


1020
TRP
N
54.662
14.460
45.484
11.94


1021
TRP
CA
54.108
13.696
46.608
12.84


1022
TRP
C
53.453
12.393
46.058
14.59


1023
TRP
O
53.073
12.404
44.901
14.57


1024
TRP
CB
53.090
14.582
47.358
12.85


1025
TRP
CG
51.796
14.668
46.559
13.65


1026
TRP
CD1
50.660
13.882
46.775
14.58


1027
TRP
CD2
51.462
15.520
45.460
12.43


1028
TRP
NE1
49.663
14.196
45.908
14.02


1029
TRP
CE2
50.123
15.214
45.098
12.63


1030
TRP
CE3
52.186
16.429
44.734
13.32


1031
TRP
CZ2
49.544
15.874
44.043
12.31


1032
TRP
CZ3
51.623
17.068
43.649
11.49


1033
TRP
CH2
50.298
16.797
43.312
14.96


1034
PRO
N
53.291
11.284
46.898
16.00


1035
PRO
CA
52.633
10.039
46.450
15.76


1036
PRO
C
51.096
10.056
46.250
16.40


1037
PRO
O
50.249
10.513
47.021
18.51


1038
PRO
CB
53.112
8.965
47.400
12.06


1039
PRO
CG
53.352
9.784
48.636
15.79


1040
PRO
CD
53.814
11.162
48.256
15.75


1041
GLN
N
50.762
9.495
45.124
18.99


1042
GLN
CA
49.356
9.444
44.808
21.65


1043
GLN
C
48.588
8.192
45.388
22.14


1044
GLN
O
47.377
8.070
45.250
20.49


1045
GLN
CB
49.477
9.419
43.309
26.00


1046
GLN
CG
49.582
10.837
42.765
32.71


1047
GLN
CD
49.147
10.778
41.328
36.57


1048
GLN
OE1
49.811
10.217
40.486
35.28


1049
GLN
NE2
47.927
11.228
41.111
40.87


1050
LYS
N
49.312
7.229
46.019
20.39


1051
LYS
CA
48.578
6.239
46.799
19.10


1052
LYS
C
49.447
5.480
47.773
16.46


1053
LYS
O
50.649
5.374
47.569
16.58


1054
LYS
CB
48.004
5.271
45.819
22.59


1055
LYS
CG
49.022
4.477
44.999
24.94


1056
LYS
CD
48.247
3.613
44.031
30.53


1057
LYS
CE
46.873
4.187
43.585
32.07


1058
LYS
NZ
46.151
3.195
42.750
40.14


1059
GLU
N
48.770
4.939
48.805
15.88


1060
GLU
CA
49.282
4.619
50.076
15.37


1061
GLU
C
50.274
3.498
49.993
15.69


1062
GLU
O
51.310
3.575
50.666
13.68


1063
GLU
CB
48.129
4.329
50.969
16.72


1064
GLU
CG
47.224
5.504
51.264
14.29


1065
GLU
CD
46.086
5.726
50.288
18.80


1066
GLU
OE1
46.254
5.591
49.071
21.62


1067
GLU
OE2
44.996
6.034
50.720
21.27


1068
GLU
N
50.001
2.488
49.145
18.42


1069
GLU
CA
50.982
1.369
48.868
20.95


1070
GLU
C
52.285
1.728
48.121
20.76


1071
GLU
O
53.234
0.936
48.094
20.49


1072
GLU
CB
50.407
0.309
47.934
20.78


1073
GLU
CG
48.890
0.282
47.935
25.93


1074
GLU
CD
48.253
1.097
46.847
25.99


1075
GLU
OE1
48.672
0.948
45.699
28.63


1076
GLU
OE2
47.378
1.916
47.165
25.53


1077
LYS
N
52.277
2.922
47.470
21.38


1078
LYS
CA
53.466
3.451
46.700
21.50


1079
LYS
C
54.120
4.756
47.250
21.97


1080
LYS
O
53.847
5.847
46.775
22.57


1081
LYS
CB
53.121
3.583
45.211
22.92


1082
LYS
CG
53.120
2.175
44.507
27.23


1083
LYS
CD
53.566
1.981
43.052
35.59


1084
LYS
CE
54.901
2.700
42.698
43.39


1085
LYS
NZ
56.064
2.530
43.615
46.48


1086
GLU
N
54.995
4.585
48.246
21.26


1087
GLU
CA
55.858
5.703
48.687
22.94


1088
GLU
C
56.922
6.019
47.618
21.77


1089
GLU
O
57.224
5.216
46.703
23.33


1090
GLU
CB
56.631
5.472
50.033
22.83


1091
GLU
CG
56.303
4.151
50.740
28.82


1092
GLU
CD
56.755
2.950
49.946
29.12


1093
GLU
OE1
57.947
2.882
49.726
33.37


1094
GLU
OE2
55.910
2.091
49.582
28.44


1095
MET
N
57.395
7.255
47.918
18.83


1096
MET
CA
58.502
7.859
47.186
17.54


1097
MET
C
59.720
7.939
48.072
19.07


1098
MET
O
59.583
8.268
49.240
20.58


1099
MET
CB
58.083
9.281
46.771
16.27


1100
MET
CG
57.088
9.220
45.629
16.56


1101
MET
SD
56.497
10.824
45.225
19.88


1102
MET
CE
57.882
11.386
44.232
18.70


1103
ILE
N
60.896
7.720
47.557
18.63


1104
ILE
CA
62.108
7.877
48.322
20.60


1105
ILE
C
63.025
8.809
47.514
20.37


1106
ILE
O
63.395
8.568
46.393
23.05


1107
ILE
CB
62.691
6.493
48.661
24.01


1108
ILE
CG1
61.881
5.871
49.811
25.81


1109
ILE
CG2
64.181
6.578
49.065
24.90


1110
ILE
CD1
61.992
4.357
49.909
27.88


1111
PHE
N
63.380
9.944
48.145
19.97


1112
PHE
CA
64.224
10.949
47.503
18.46


1113
PHE
C
65.685
10.633
47.905
19.73


1114
PHE
O
66.114
10.938
49.001
18.94


1115
PHE
CB
63.753
12.370
47.917
16.35


1116
PHE
CG
62.290
12.582
47.628
14.87


1117
PHE
CD1
61.851
12.931
46.357
13.55


1118
PHE
CD2
61.348
12.399
48.607
16.14


1119
PHE
CE1
60.511
13.044
46.035
14.72


1120
PHE
CE2
60.000
12.519
48.297
14.63


1121
PHE
CZ
59.565
12.811
47.004
14.92


1122
GLU
N
66.423
9.955
47.009
23.42


1123
GLU
CA
67.730
9.355
47.371
27.04


1124
GLU
C
68.809
10.381
47.518
26.67


1125
GLU
O
69.611
10.299
48.440
27.77


1126
GLU
CB
68.229
8.253
46.431
32.84


1127
GLU
CG
67.362
6.947
46.395
43.59


1128
GLU
CD
68.029
5.711
45.646
52.36


1129
GLU
OE1
68.362
5.845
44.439
54.69


1130
GLU
OE2
68.199
4.647
46.298
55.07


1131
ASP
N
68.765
11.386
46.636
25.27


1132
ASP
CA
69.664
12.544
46.813
24.77


1133
ASP
C
69.573
13.322
48.180
24.82


1134
ASP
O
70.550
13.880
48.657
26.69


1135
ASP
CB
69.487
13.507
45.649
25.87


1136
ASP
CG
68.195
14.296
45.612
28.11


1137
ASP
OD1
67.142
13.727
45.835
27.95


1138
ASP
OD2
68.296
15.481
45.365
30.09


1139
THR
N
68.365
13.360
48.766
22.69


1140
THR
CA
68.270
13.979
50.054
20.10


1141
THR
C
67.933
13.020
51.178
20.10


1142
THR
O
67.943
13.373
52.347
20.15


1143
THR
CB
67.476
15.268
50.010
18.17


1144
THR
OG1
66.041
14.985
49.980
15.16


1145
THR
CG2
68.214
16.309
49.052
16.50


1146
ASN
N
67.735
11.756
50.863
21.38


1147
ASN
CA
67.628
10.783
51.969
23.28


1148
ASN
C
66.346
10.889
52.861
23.35


1149
ASN
O
66.353
10.887
54.078
24.28


1150
ASN
CB
68.918
10.815
52.831
27.97


1151
ASN
CG
69.285
9.445
53.414
32.19


1152
ASN
OD1
68.963
8.394
52.899
34.42


1153
ASN
ND2
70.048
9.471
54.465
31.14


1154
LEU
N
65.246
10.944
52.152
22.74


1155
LEU
CA
63.923
11.233
52.687
21.67


1156
LEU
C
62.917
10.253
52.009
20.94


1157
LEU
O
62.978
9.941
50.835
21.39


1158
LEU
CB
63.586
12.665
52.212
21.84


1159
LEU
CG
63.600
13.787
53.240
23.27


1160
LEU
CD1
64.055
15.113
52.656
17.13


1161
LEU
CD2
64.224
13.472
54.596
21.62


1162
LYS
N
61.974
9.802
52.783
21.10


1163
LYS
CA
60.920
8.934
52.328
19.53


1164
LYS
C
59.609
9.681
52.550
18.34


1165
LYS
O
59.486
10.402
53.520
20.22


1166
LYS
CB
61.135
7.645
53.185
20.94


1167
LYS
CG
59.973
6.657
53.250
22.87


1168
LYS
CD
60.414
5.282
53.669
29.27


1169
LYS
CE
59.161
4.429
53.683
32.16


1170
LYS
NZ
59.380
3.130
54.360
36.84


1171
LEU
N
58.659
9.543
51.618
16.41


1172
LEU
CA
57.406
10.345
51.727
16.41


1173
LEU
C
56.161
9.462
51.429
16.89


1174
LEU
O
56.112
8.863
50.367
16.71


1175
LEU
CB
57.542
11.526
50.777
15.09


1176
LEU
CG
56.271
12.369
50.729
13.98


1177
LEU
CD1
56.382
13.211
49.453
15.42


1178
LEU
CD2
56.090
13.271
51.990
16.75


1179
THR
N
55.183
9.368
52.377
17.65


1180
THR
CA
54.124
8.352
52.362
17.51


1181
THR
C
52.766
9.036
52.409
16.95


1182
THR
O
52.566
9.943
53.206
16.10


1183
THR
CB
54.424
7.325
53.497
15.94


1184
THR
OG1
55.871
7.204
53.749
15.73


1185
THR
CG2
54.295
5.897
53.009
17.67


1186
LEU
N
51.815
8.672
51.504
15.85


1187
LEU
CA
50.464
9.240
51.601
16.51


1188
LEU
C
49.849
8.492
52.784
19.83


1189
LEU
O
49.757
7.284
52.720
20.59


1190
LEU
CB
49.614
9.054
50.317
15.58


1191
LEU
CG
48.211
9.745
50.328
15.08


1192
LEU
CD1
47.345
9.428
49.092
13.12


1193
LEU
CD2
48.368
11.251
50.477
15.75


1194
ILE
N
49.561
9.233
53.881
18.46


1195
ILE
CA
48.795
8.626
54.964
18.30


1196
ILE
C
47.299
8.487
54.699
18.81


1197
ILE
O
46.786
7.492
55.168
19.41


1198
ILE
CB
49.008
9.309
56.286
17.44


1199
ILE
CG1
50.497
9.177
56.670
16.16


1200
ILE
CG2
48.030
8.763
57.336
17.37


1201
ILE
OD1
51.109
7.804
56.438
15.26


1202
SER
N
46.772
9.561
54.052
18.02


1203
SER
CA
45.404
9.579
53.498
19.40


1204
SER
C
45.002
10.838
52.741
21.38


1205
SER
O
45.731
11.814
52.767
22.64


1206
SER
CB
44.410
9.580
54.635
21.28


1207
SER
OG
44.258
10.789
55.488
24.51


1208
GLU
N
43.804
10.869
52.157
22.91


1209
GLU
CA
43.247
12.165
51.666
25.57


1210
GLU
C
41.728
12.456
51.777
25.11


1211
GLU
O
40.921
11.581
51.933
28.12


1212
GLU
CB
43.646
12.377
50.247
27.94


1213
GLU
CG
43.357
11.238
49.297
32.29


1214
GLU
CD
44.066
11.603
47.994
38.30


1215
GLU
OE1
44.307
12.793
47.744
43.02


1216
GLU
OE2
44.430
10.703
47.259
41.87


1217
ASP
N
41.337
13.722
51.692
20.31


1218
ASP
CA
39.977
14.185
51.811
18.75


1219
ASP
C
39.742
15.051
50.582
19.30


1220
ASP
O
40.185
16.193
50.485
17.85


1221
ASP
CB
40.000
14.960
53.115
21.92


1222
ASP
CG
38.796
15.833
53.455
28.13


1223
ASP
OD1
37.691
15.542
52.994
28.01


1224
ASP
OD2
38.979
16.828
54.204
33.77


1225
ILE
N
39.104
14.403
49.603
19.47


1226
ILE
CA
38.862
15.024
48.297
20.98


1227
ILE
C
37.511
15.728
48.182
22.51


1228
ILE
O
36.486
15.086
48.315
25.15


1229
ILE
CB
38.844
13.927
47.248
22.51


1230
ILE
CG1
40.112
13.113
47.366
22.32


1231
ILE
CG2
38.613
14.468
45.803
23.73


1232
ILE
CD1
40.193
12.123
46.229
22.61


1233
LYS
N
37.553
17.021
47.906
21.11


1234
LYS
CA
36.359
17.863
47.866
20.45


1235
LYS
C
36.188
18.316
46.391
20.80


1236
LYS
O
37.064
18.038
45.587
22.26


1237
LYS
CB
36.663
18.921
48.924
22.37


1238
LYS
CG
36.755
18.276
50.320
25.62


1239
LYS
CD
35.354
18.201
50.911
29.83


1240
LYS
CE
35.212
17.510
52.277
33.05


1241
LYS
NZ
33.797
17.735
52.656
35.32


1242
THR
N
35.094
18.956
45.972
19.82


1243
THR
CA
34.963
19.315
44.853
21.59


1244
THR
C
35.971
20.151
44.101
20.83


1245
THR
O
36.245
19.955
42.922
22.59


1246
THR
CB
33.646
20.055
44.669
24.13


1247
THR
OG1
33.609
21.266
45.395
24.73


1248
THR
CG2
32.537
19.144
45.139
30.44


1249
TYR
N
36.550
21.088
44.859
17.73


1250
TYR
CA
37.522
21.987
44.234
15.97


1251
TYR
C
38.926
22.037
44.888
15.46


1252
TYR
O
39.790
22.830
44.552
15.86


1253
TYR
CB
36.862
23.362
44.168
12.55


1254
TYR
CG
36.787
24.053
45.510
12.56


1255
TYR
CD1
35.748
23.758
46.416
14.70


1256
TYR
CD2
37.745
25.026
45.793
14.86


1257
TYR
CE1
35.638
24.506
47.593
15.48


1258
TYR
CE2
37.676
25.747
47.000
16.69


1259
TYR
CZ
36.598
25.497
47.858
16.96


1260
TYR
OH
36.474
26.267
48.979
15.71


1261
TYR
N
39.089
21.152
45.889
14.74


1262
TYR
CA
40.333
21.010
46.643
14.03


1263
TYR
C
40.453
19.639
47.315
16.12


1264
TYR
O
39.469
18.949
47.536
17.82


1265
TYR
CB
40.575
22.195
47.613
12.74


1266
TYR
CG
39.769
22.161
48.905
15.40


1267
TYR
CD1
40.334
21.536
50.033
13.77


1268
TYR
CD2
38.479
22.734
48.947
18.58


1269
TYR
CE1
39.560
21.424
51.207
15.81


1270
TYR
CE2
37.715
22.646
50.134
17.84


1271
TYR
CZ
38.266
21.965
51.235
16.69


1272
TYR
OH
37.544
21.811
52.389
18.92


1273
THR
N
41.697
19.226
47.627
14.21


1274
THR
CA
41.956
17.974
48.377
15.42


1275
THR
C
42.951
18.234
49.465
15.44


1276
THR
O
43.955
18.887
49.248
15.14


1277
THR
CB
42.630
16.919
47.491
16.15


1278
THR
OG1
41.761
16.554
46.440
16.75


1279
THR
CG2
43.128
15.643
48.159
15.21


1280
VAL
N
42.638
17.716
50.607
14.25


1281
VAL
CA
43.604
17.716
51.687
15.61


1282
VAL
C
44.212
16.325
51.849
15.76


1283
VAL
O
43.534
15.320
51.815
16.87


1284
VAL
CB
42.971
18.215
53.028
15.56


1285
VAL
CG1
42.210
19.534
52.861
17.93


1286
VAL
CG2
44.018
18.329
54.147
15.84


1287
ARG
N
45.545
16.296
51.981
15.23


1288
ARG
CA
46.259
15.034
52.198
12.90


1289
ARG
C
47.094
15.095
53.452
14.57


1290
ARG
O
47.669
16.099
53.852
14.51


1291
ARG
CB
47.213
14.689
51.060
12.22


1292
ARG
CG
46.431
14.664
49.771
14.22


1293
ARG
CD
47.328
14.307
48.603
17.43


1294
ARG
NE
46.522
14.288
47.372
19.70


1295
ARG
CZ
46.343
15.286
46.563
18.02


1296
ARG
NH1
46.936
16.433
46.719
20.75


1297
ARG
NH2
45.562
15.101
45.583
22.30


1298
GLN
N
47.167
13.949
54.075
15.95


1299
GLN
CA
48.177
13.855
55.083
15.20


1300
GLN
C
49.286
12.980
54.578
14.98


1301
GLN
O
49.094
11.915
54.000
15.16


1302
GLN
CB
47.425
13.295
56.248
19.99


1303
GLN
CG
48.352
12.986
57.366
24.39


1304
GLN
CD
47.446
12.294
58.357
33.29


1305
GLN
OE1
46.290
11.917
58.100
36.18


1306
GLN
NE2
48.061
12.057
59.508
32.20


1307
LEU
N
50.472
13.510
54.813
14.40


1308
LEU
CA
51.690
12.890
54.351
16.50


1309
LEU
C
52.629
12.588
55.537
17.55


1310
LEU
O
52.702
13.268
56.555
18.19


1311
LEU
CB
52.425
13.840
53.397
16.87


1312
LEU
CG
52.057
14.029
51.920
19.16


1313
LEU
CD1
52.220
15.473
51.494
18.62


1314
LEU
CD2
50.780
13.408
51.439
19.45


1315
GLU
N
53.373
11.519
55.358
16.26


1316
GLU
CA
54.428
11.311
56.300
16.63


1317
GLU
C
55.754
11.455
55.632
15.84


1318
GLU
O
56.066
10.787
54.676
17.35


1319
GLU
CB
54.304
9.947
56.958
17.38


1320
GLU
CG
55.477
9.848
57.928
23.65


1321
GLU
CD
55.430
8.583
58.764
30.56


1322
GLU
OE1
54.547
8.475
59.626
31.25


1323
GLU
OE2
56.295
7.734
58.553
32.96


1324
LEU
N
56.529
12.352
56.152
17.81


1325
LEU
CA
57.907
12.582
55.715
19.00


1326
LEU
C
58.902
11.990
56.739
21.54


1327
LEU
O
59.000
12.436
57.883
19.81


1328
LEU
CB
58.084
14.121
55.646
17.55


1329
LEU
CG
59.011
14.839
54.653
19.65


1330
LEU
CD1
59.999
13.982
53.910
20.83


1331
LEU
CD2
59.611
16.118
55.230
17.35


1332
GLU
N
59.677
11.018
56.242
24.40


1333
GLU
CA
60.757
10.444
57.062
24.80


1334
GLU
C
62.183
10.790
56.622
25.64


1335
GLU
O
62.666
10.593
55.508
24.49


1336
GLU
CB
60.566
8.923
57.182
24.55


1337
GLU
CG
61.533
8.201
58.134
26.49


1338
GLU
CD
61.368
6.701
58.012
28.97


1339
GLU
OE1
60.447
6.223
57.350
33.55


1340
GLU
OE2
62.199
5.969
58.536
32.02


1341
ASN
N
62.873
11.339
57.617
26.33


1342
ASN
CA
64.303
11.526
57.452
28.36


1343
ASN
C
65.008
10.195
57.582
29.60


1344
ASN
O
65.247
9.741
58.682
31.34


1345
ASN
CB
64.793
12.543
58.488
27.93


1346
ASN
CG
66.295
12.759
58.412
30.21


1347
ASN
OD1
67.105
11.921
58.046
28.62


1348
ASN
ND2
66.668
13.937
58.851
31.76


1349
LEU
N
65.339
9.597
56.434
30.56


1350
LEU
CA
65.970
8.276
56.397
31.30


1351
LEU
C
67.360
8.191
57.066
35.28


1352
LEU
O
67.827
7.146
57.488
35.62


1353
LEU
CB
66.080
7.880
54.942
28.95


1354
LEU
CG
65.153
6.811
54.458
29.38


1355
LEU
CD1
65.096
6.740
52.927
27.85


1356
LEU
CD2
63.794
6.896
55.086
30.00


1357
THR
N
68.009
9.367
57.192
37.71


1358
THR
CA
69.278
9.474
57.935
41.16


1359
THR
C
69.130
9.189
59.443
43.17


1360
THR
O
70.010
8.733
60.157
45.18


1361
THR
CB
69.921
10.888
57.739
44.16


1362
THR
OG1
70.079
11.267
56.353
45.45


1363
THR
CG2
71.278
11.033
58.430
44.74


1364
THR
N
67.912
9.502
59.928
43.51


1365
THR
CA
67.627
9.396
61.373
40.76


1366
THR
C
66.443
8.517
61.738
41.34


1367
THR
O
66.193
8.141
62.866
43.02


1368
THR
CB
67.386
10.777
62.009
39.25


1369
THR
OG1
66.206
11.364
61.461
42.09


1370
THR
CG2
68.536
11.758
61.802
37.92


1371
GLN
N
65.653
8.252
60.722
40.94


1372
GLN
CA
64.289
7.831
61.000
41.20


1373
GLN
C
63.388
8.708
61.881
38.70


1374
GLN
O
62.322
8.304
62.315
38.13


1375
GLN
CB
64.284
6.380
61.408
45.37


1376
GLN
CG
64.898
5.645
60.250
51.51


1377
GLN
CD
64.977
4.182
60.571
56.44


1378
GLN
CE1
65.018
3.741
61.710
58.04


1379
GLN
NE2
65.051
3.403
59.497
61.09


1380
GLU
N
63.785
9.974
62.092
37.29


1381
GLU
CA
62.727
10.920
62.488
37.74


1382
GLU
C
61.627
11.026
61.422
35.73


1383
GLU
O
61.806
10.869
60.217
34.94


1384
GLU
CB
63.277
12.311
62.903
43.18


1385
GLU
CG
62.269
13.276
63.617
51.01


1386
GLU
CD
62.855
14.683
63.932
57.11


1387
GLU
OE1
64.057
14.771
64.282
59.70


1388
GLU
OE2
62.106
15.688
63.812
59.23


1389
THR
N
60.452
11.227
61.976
33.44


1390
THR
CA
59.253
11.210
61.132
31.67


1391
THR
C
58.364
12.397
61.416
30.34


1392
THR
O
58.213
12.814
62.569
31.62


1393
THR
CB
58.498
9.890
61.287
29.52


1394
THR
OG1
58.650
9.203
60.065
31.41


1395
THR
CG2
57.054
9.944
61.745
27.83


1396
ARG
N
57.809
12.940
60.314
27.40


1397
ARG
CA
56.900
14.072
60.476
22.96


1398
ARG
C
55.656
14.011
59.676
19.60


1399
ARG
O
55.670
13.570
58.544
18.08


1400
ARG
CB
57.517
15.400
60.125
24.02


1401
ARG
CG
58.772
15.656
60.892
27.06


1402
ARG
CD
59.108
17.126
60.821
30.34


1403
ARG
NE
60.299
17.280
61.631
31.08


1404
ARG
CZ
61.259
18.051
61.210
33.27


1405
ARG
NH1
61.083
18.824
60.138
28.01


1406
ARG
NH2
62.397
17.980
61.904
34.77


1407
GLU
N
54.607
14.560
60.263
19.61


1408
GLU
CA
53.391
14.722
59.470
20.49


1409
GLU
C
53.307
16.068
58.787
18.35


1410
GLU
O
53.451
17.113
59.403
19.50


1411
GLU
CB
52.147
14.576
60.334
23.73


1412
GLU
CG
50.804
14.805
59.633
30.58


1413
GLU
CD
49.709
15.110
60.669
37.37


1414
GLU
OE1
49.895
15.928
61.586
42.91


1415
GLU
OE2
48.642
14.550
60.567
39.95


1416
ILE
N
53.037
15.988
57.502
17.31


1417
ILE
CA
52.824
17.183
56.671
15.44


1418
ILE
C
51.428
17.188
56.122
13.03


1419
ILE
O
50.984
16.205
55.574
13.73


1420
ILE
CB
53.864
17.224
55.509
14.77


1421
ILE
CG1
55.351
17.051
55.964
13.99


1422
ILE
CG2
53.605
18.469
54.616
13.81


1423
ILE
CD1
56.011
18.081
56.937
13.39


1424
LEU
N
50.739
18.290
56.267
9.92


1425
LEU
CA
49.468
18.427
55.596
10.85


1426
LEU
C
49.617
19.120
54.238
12.45


1427
LEU
O
50.280
20.137
54.100
13.72


1428
LEU
CB
48.604
19.334
56.441
11.52


1429
LEU
CG
47.671
18.670
57.476
17.76


1430
LEU
CD1
47.397
19.618
58.652
14.86


1431
LEU
CD2
48.036
17.234
57.826
15.60


1432
HIS
N
48.967
18.566
53.225
10.68


1433
HIS
CA
49.032
19.147
51.860
11.55


1434
HIS
C
47.653
19.632
51.485
12.79


1435
HIS
O
46.691
18.863
51.473
14.70


1436
HIS
CB
49.509
18.015
50.917
11.04


1437
HIS
CG
49.846
18.414
49.500
9.68


1438
HIS
ND1
49.049
18.115
48.481
10.25


1439
HIS
CD2
50.975
19.042
49.048
10.64


1440
HIS
CE1
49.666
18.552
47.378
12.62


1441
HIS
NE2
50.846
19.126
47.727
11.21


1442
PHE
N
47.569
20.948
51.199
12.23


1443
PHE
CA
46.274
21.521
50.815
10.89


1444
PHE
C
46.347
21.882
49.348
13.34


1445
PHE
O
47.133
22.727
48.947
13.55


1446
PHE
CB
45.985
22.804
51.608
10.80


1447
PHE
CG
46.010
22.514
53.082
11.64


1448
PHE
CD1
47.239
22.635
53.771
11.60


1449
PHE
CD2
44.825
22.131
53.751
14.48


1450
PHE
CE1
47.320
22.342
55.132
12.91


1451
PHE
CE2
44.901
21.852
55.142
15.96


1452
PHE
CZ
46.143
21.936
55.791
13.40


1453
HIS
N
45.551
21.162
48.554
11.63


1454
HIS
CA
45.637
21.261
47.102
10.69


1455
HIS
C
44.419
21.873
46.463
11.28


1456
HIS
O
43.339
21.303
46.375
10.79


1457
HIS
CB
45.985
19.871
46.547
11.78


1458
HIS
CG
46.316
19.861
45.068
10.24


1459
HIS
ND1
46.407
20.911
44.219
13.45


1460
HIS
CD2
46.596
18.751
44.321
9.09


1461
HIS
CE1
46.724
20.470
42.970
8.49


1462
HIS
NE2
46.847
19.132
43.028
12.97


1463
TYR
N
44.598
23.139
46.037
10.13


1464
TYR
CA
43.496
23.797
45.360
11.53


1465
TYR
C
43.543
23.415
43.888
12.75


1466
TYR
O
44.543
23.620
43.217
11.94


1467
TYR
CB
43.699
25.310
45.529
12.91


1468
TYR
CG
42.453
26.186
45.414
14.41


1469
TYR
CD1
41.617
26.161
44.267
12.62


1470
TYR
CD2
42.190
27.059
46.496
14.67


1471
TYR
CE1
40.497
27.009
44.203
14.22


1472
TYR
CE2
41.062
27.896
46.437
15.77


1473
TYR
CZ
40.224
27.857
45.292
16.57


1474
TYR
OH
39.121
28.676
45.247
18.08


1475
THR
N
42.470
22.797
43.411
13.66


1476
THR
CA
42.557
22.223
42.056
14.87


1477
THR
C
41.794
22.989
40.931
16.37


1478
THR
O
41.788
22.650
39.752
19.74


1479
THR
CB
42.122
20.752
42.107
13.92


1480
THR
OG1
40.780
20.610
42.619
14.21


1481
THR
CG2
43.091
19.964
42.981
14.13


1482
THR
N
41.108
24.086
41.337
17.79


1483
THR
CA
40.223
24.849
40.406
17.71


1484
THR
C
40.545
26.343
40.315
17.22


1485
THR
O
39.717
27.169
39.955
19.49


1486
THR
CB
38.737
24.756
40.818
20.00


1487
THR
OG1
38.645
25.274
42.134
22.57


1488
THR
CG2
38.165
23.331
40.809
17.86


1489
TRP
N
41.824
26.648
40.637
13.24


1490
TRP
CA
42.325
28.014
40.474
11.42


1491
TRP
C
43.192
28.106
39.219
11.23


1492
TRP
O
44.305
27.599
39.146
13.88


1493
TRP
CB
43.175
28.346
41.714
10.59


1494
TRP
CG
43.522
29.827
41.830
10.86


1495
TRP
CD1
43.572
30.834
40.839
10.44


1496
TRP
CD2
43.944
30.486
43.029
11.23


1497
TRP
NE1
43.985
32.030
41.334
11.38


1498
TRP
CE2
44.223
31.860
42.696
11.59


1499
TRP
CE3
44.121
30.010
44.341
12.73


1500
TRP
CZ2
44.674
32.751
43.694
9.06


1501
TRP
CZ3
44.569
30.912
45.324
11.86


1502
TRP
CH2
44.846
32.248
45.002
9.08


1503
PRO
N
42.673
28.737
38.174
11.63


1504
PRO
CA
43.454
28.717
36.926
12.03


1505
PRO
C
44.752
29.544
36.926
10.91


1506
PRO
O
44.841
30.605
37.525
11.74


1507
PRO
CB
42.440
29.259
35.916
15.45


1508
PRO
CG
41.096
29.392
36.622
16.92


1509
PRO
CD
41.398
29.448
38.084
12.40


1510
ASP
N
45.746
29.023
36.201
9.83


1511
ASP
CA
46.936
29.819
36.018
13.50


1512
ASP
C
46.686
31.178
35.371
15.42


1513
ASP
O
45.875
31.324
34.474
16.15


1514
ASP
CB
47.954
29.031
35.195
14.19


1515
ASP
CG
49.381
29.475
35.461
17.10


1516
ASP
OD1
49.628
30.416
36.256
16.38


1517
ASP
OD2
50.271
28.847
34.883
16.84


1518
PHE
N
47.308
32.203
35.958
15.66


1519
PHE
CA
46.951
33.601
35.630
13.22


1520
PHE
C
45.496
34.007
35.774
13.65


1521
PHE
O
45.036
34.974
35.189
14.13


1522
PHE
CB
47.522
33.989
34.243
15.03


1523
PHE
CG
49.046
33.819
34.221
16.37


1524
PHE
CD1
49.875
34.865
34.737
12.85


1525
PHE
CD2
49.590
32.627
33.669
15.04


1526
PHE
CE1
51.275
34.714
34.723
10.54


1527
PHE
CE2
50.986
32.515
33.639
12.82


1528
PHE
CZ
51.798
33.547
34.161
12.68


1529
GLY
N
44.790
33.186
36.600
12.17


1530
GLY
CA
43.402
33.477
36.870
12.74


1531
GLY
C
43.130
33.699
38.349
13.53


1532
GLY
O
44.023
33.939
39.149
12.80


1533
VAL
N
41.854
33.622
38.691
14.29


1534
VAL
CA
41.352
33.878
40.056
13.36


1535
VAL
C
40.477
32.685
40.533
15.85


1536
VAL
O
39.970
31.920
39.707
16.84


1537
VAL
CB
40.533
35.165
40.144
12.64


1538
VAL
CG1
39.246
35.111
39.297
13.96


1539
VAL
CG2
41.357
36.379
39.842
12.56


1540
PRO
N
40.310
32.541
41.888
16.09


1541
PRO
CA
39.326
31.553
42.374
14.29


1542
PRO
C
37.904
31.850
41.841
16.70


1543
PRO
O
37.538
32.942
41.394
15.47


1544
PRO
CB
39.425
31.709
43.893
12.24


1545
PRO
CG
40.797
32.289
44.158
11.83


1546
PRO
CD
41.011
33.237
42.981
14.99


1547
GLU
N
37.091
30.811
41.895
18.37


1548
GLU
CA
35.721
30.970
41.414
20.99


1549
GLU
C
34.895
32.053
42.123
22.01


1550
GLU
O
34.014
32.699
41.571
24.26


1551
GLU
CB
34.978
29.614
41.414
22.54


1552
GLU
CG
35.941
28.443
41.162
31.50


1553
GLU
CD
36.522
27.764
42.465
36.66


1554
GLU
OE1
37.244
28.386
43.315
31.28


1555
GLU
OE2
36.201
26.562
42.601
36.17


1556
SER
N
35.218
32.225
43.432
20.38


1557
SER
CA
34.520
33.218
44.274
17.88


1558
SER
C
35.369
33.535
45.449
15.08


1559
SER
O
36.146
32.701
45.885
14.67


1560
SER
CB
33.107
32.739
44.793
16.14


1561
SER
OG
33.172
31.454
45.419
13.25


1562
PRO
N
35.198
34.731
46.003
17.02


1563
PRO
CA
35.695
34.996
47.370
16.44


1564
PRO
C
35.343
33.936
48.410
16.53


1565
PRO
O
36.174
33.495
49.169
15.74


1566
PRO
CB
35.085
36.348
47.744
16.53


1567
PRO
CG
34.912
37.008
46.367
18.72


1568
PRO
CD
34.518
35.878
45.431
16.72


1569
ALA
N
34.112
33.456
48.396
16.66


1570
ALA
CA
33.729
32.357
49.341
16.12


1571
ALA
C
34.496
31.057
49.241
15.23


1572
ALA
O
34.901
30.462
50.211
15.53


1573
ALA
CB
32.226
31.970
49.232
15.29


1574
SER
N
34.701
30.625
48.006
15.32


1575
SER
CA
35.478
29.414
47.823
15.79


1576
SER
C
36.944
29.511
48.170
13.45


1577
SER
O
37.543
28.637
48.804
13.08


1578
SER
CB
35.222
28.779
46.447
17.95


1579
SER
OG
35.486
29.689
45.407
26.88


1580
PHE
N
37.464
30.720
47.831
13.85


1581
PHE
CA
38.864
31.032
48.219
12.76


1582
PHE
C
39.021
31.081
49.708
12.10


1583
PHE
O
39.917
30.465
50.247
14.79


1584
PHE
CB
39.297
32.409
47.672
14.01


1585
PHE
CG
40.660
32.843
48.229
12.89


1586
PHE
CD1
41.853
32.277
47.736
10.70


1587
PHE
CD2
40.701
33.811
49.277
15.33


1588
PHE
CE1
43.092
32.636
48.324
13.65


1589
PHE
CE2
41.935
34.193
49.864
13.88


1590
PHE
CZ
43.111
33.585
49.388
14.38


1591
LEU
N
38.112
31.849
50.367
13.17


1592
LEU
CA
38.075
32.020
51.857
11.98


1593
LEU
C
37.823
30.760
52.651
11.69


1594
LEU
O
38.520
30.483
53.608
10.86


1595
LEU
CB
37.066
33.104
52.284
11.49


1596
LEU
CG
37.504
34.528
51.922
9.71


1597
LEU
CD1
38.642
35.024
52.815
12.65


1598
LEU
CD2
36.326
35.472
51.928
12.34


1599
ASN
N
36.872
29.960
52.146
13.52


1600
ASN
CA
36.726
28.586
52.660
14.70


1601
ASN
C
38.019
27.745
52.629
13.68


1602
ASN
O
38.453
27.118
53.596
13.48


1603
ASN
CB
35.555
27.891
51.921
15.31


1604
ASN
CG
35.254
26.492
52.493
16.04


1605
ASN
OD1
34.760
26.270
53.576
17.67


1606
ASN
ND2
35.582
25.465
51.694
15.77


1607
PHE
N
38.701
27.785
51.452
12.27


1608
PHE
CA
39.997
27.082
51.440
11.60


1609
PHE
C
41.052
27.661
52.365
11.61


1610
PHE
O
41.697
26.908
53.084
13.15


1611
PHE
CB
40.490
27.042
49.979
11.94


1612
PHE
CG
41.868
26.456
49.776
11.78


1613
PHE
CD1
43.009
27.294
49.766
14.00


1614
PHE
CD2
42.033
25.070
49.586
11.64


1615
PHE
CE1
44.296
26.727
49.592
10.61


1616
PHE
CE2
43.329
24.515
49.407
12.07


1617
PHE
CZ
44.460
25.345
49.407
10.24


1618
LEU
N
41.208
29.021
52.358
10.72


1619
LEU
CA
42.131
29.689
53.281
10.36


1620
LEU
C
41.892
29.328
54.775
11.41


1621
LEU
O
42.776
29.036
55.575
8.72


1622
LEU
CB
42.039
31.214
53.107
9.30


1623
LEU
CG
42.908
32.004
54.144
11.24


1624
LEU
CD1
42.781
33.509
53.999
9.97


1625
LEU
CD2
44.376
31.595
54.123
8.08


1626
PHE
N
40.589
29.343
55.118
13.37


1627
PHE
CA
40.178
28.962
56.483
14.13


1628
PHE
C
40.391
27.509
56.789
14.10


1629
PHE
O
40.855
27.222
57.866
16.46


1630
PHE
CB
38.766
29.443
56.760
14.59


1631
PHE
CG
38.772
30.884
57.201
17.38


1632
PHE
CD1
39.357
31.890
56.414
17.66


1633
PHE
CD2
38.132
31.220
58.421
20.46


1634
PHE
CE1
39.363
33.222
56.859
17.85


1635
PHE
CE2
38.121
32.566
58.855
21.97


1636
PHE
CZ
38.761
33.551
58.091
19.00


1637
LYS
N
40.227
26.595
55.788
14.03


1638
LYS
CA
40.694
25.200
56.007
13.68


1639
LYS
C
42.139
25.064
56.362
13.76


1640
LYS
O
42.514
24.340
57.275
13.17


1641
LYS
CB
40.525
24.284
54.793
17.74


1642
LYS
CG
39.416
23.233
54.857
26.69


1643
LYS
CD
39.759
21.835
55.418
32.82


1644
LYS
CE
38.482
20.926
55.564
34.45


1645
LYS
NZ
38.794
19.520
55.920
39.18


1646
VAL
N
43.001
25.790
55.589
13.89


1647
VAL
CA
44.422
25.885
55.972
11.86


1648
VAL
C
44.678
26.442
57.355
11.86


1649
VAL
O
45.304
25.794
58.182
11.98


1650
VAL
CB
45.238
26.728
54.971
12.00


1651
VAL
CG1
44.967
26.260
53.509
11.88


1652
VAL
CG2
46.748
26.651
55.285
12.37


1653
ARG
N
44.126
27.628
57.609
12.93


1654
ARG
CA
44.218
28.196
58.973
14.48


1655
ARG
C
43.774
27.269
60.139
16.45


1656
ARG
O
44.486
27.063
61.113
17.22


1657
ARG
CB
43.366
29.447
59.011
13.76


1658
ARG
CG
44.037
30.657
58.430
12.22


1659
ARG
CD
43.028
31.823
58.494
13.67


1660
ARG
NE
43.712
33.077
58.134
15.68


1661
ARG
CZ
43.554
34.198
58.799
14.21


1662
ARG
NH1
42.626
34.342
59.706
12.91


1663
ARG
NH2
44.379
35.143
58.580
12.03


1664
GLU
N
42.622
26.635
59.960
16.23


1665
GLU
CA
42.097
25.723
60.976
16.92


1666
GLU
C
42.975
24.566
61.298
16.63


1667
GLU
O
43.037
24.051
62.388
17.05


1668
GLU
CB
40.849
25.081
60.476
21.77


1669
GLU
CG
39.696
26.051
60.316
30.11


1670
GLU
CD
38.885
26.144
61.587
37.62


1671
GLU
OE1
38.166
27.160
61.732
42.75


1672
GLU
OE2
38.978
25.220
62.436
39.25


1673
SER
N
43.731
24.148
60.295
16.50


1674
SER
CA
44.592
22.981
60.481
17.63


1675
SER
C
45.788
23.113
61.450
20.41


1676
SER
O
46.550
22.181
61.695
21.90


1677
SER
CB
45.172
22.503
59.108
14.84


1678
SER
OG
46.254
23.396
58.735
13.92


1679
GLY
N
46.011
24.359
61.919
20.72


1680
GLY
CA
47.237
24.604
62.671
20.75


1681
GLY
C
48.494
24.856
61.883
22.62


1682
GLY
O
49.516
25.236
62.431
25.75


1683
SER
N
48.416
24.672
60.541
20.77


1684
SER
CA
49.659
24.779
59.772
20.37


1685
SER
C
50.360
26.137
59.773
22.30


1686
SER
O
51.559
26.233
59.585
22.94


1687
SER
CB
49.485
24.400
58.287
17.21


1688
SER
OG
49.026
23.044
58.151
16.17


1689
LEU
N
49.548
27.204
59.963
22.44


1690
LEU
CA
50.024
28.615
59.942
25.58


1691
LEU
C
50.572
29.143
64.293
29.18


1692
LEU
O
50.849
30.302
61.553
34.54


1693
LEU
CB
48.951
29.616
59.439
23.62


1694
LEU
CG
48.548
29.235
58.027
22.66


1695
LEU
CD1
49.689
29.422
57.098
23.63


1696
LEU
CD2
47.444
30.047
57.437
25.59


1697
SER
N
50.649
28.205
62.203
27.88


1698
SER
CA
50.934
28.588
63.544
28.98


1699
SER
C
52.365
28.767
63.829
29.17


1700
SER
O
53.212
28.114
63.230
29.28


1701
SER
CB
50.428
27.503
64.367
29.56


1702
SER
OG
49.070
27.851
64.442
38.82


1703
PRO
N
52.649
29.669
64.766
28.99


1704
PRO
CA
54.068
29.983
64.955
28.15


1705
PRO
C
54.893
28.912
65.712
27.34


1706
PRO
O
56.103
28.986
65.759
28.43


1707
PRO
CB
53.940
31.338
65.624
29.14


1708
PRO
CG
52.734
31.150
66.539
28.91


1709
PRO
CD
51.769
30.350
65.692
28.77


1710
GLU
N
54.222
27.885
66.248
25.89


1711
GLU
CA
54.930
26.738
66.757
27.19


1712
GLU
C
55.561
25.818
65.688
26.00


1713
GLU
O
56.405
24.951
65.946
25.89


1714
GLU
CB
54.031
26.017
67.792
33.55


1715
GLU
CG
52.691
25.276
67.504
41.02


1716
GLU
CD
51.512
26.145
67.001
47.74


1717
GLU
OE1
51.521
27.382
67.117
49.25


1718
GLU
OE2
50.550
25.570
66.459
51.04


1719
HIS
N
55.110
26.077
64.437
21.92


1720
HIS
CA
55.663
25.415
63.239
18.96


1721
HIS
C
56.588
26.312
62.464
17.83


1722
HIS
O
56.466
27.528
62.564
17.07


1723
HIS
CB
54.545
25.023
62.270
20.94


1724
HIS
CG
53.668
24.065
63.047
20.70


1725
HIS
ND1
52.366
24.242
63.288
22.42


1726
HIS
CD2
54.077
22.872
63.652
19.89


1727
HIS
CE1
51.937
23.170
64.033
18.97


1728
HIS
NE2
52.998
22.336
64.244
19.93


1729
GLY
N
57.430
25.669
61.628
16.31


1730
GLY
CA
58.102
26.449
60.582
14.07


1731
GLY
C
57.110
27.069
59.607
12.35


1732
GLY
O
55.911
26.804
59.695
13.46


1733
PRO
N
57.602
27.933
58.693
11.56


1734
PRO
CA
56.641
28.612
57.833
13.06


1735
PRO
C
55.989
27.621
56.834
12.70


1736
PRO
O
56.633
26.687
56.321
13.68


1737
PRO
CB
57.455
29.724
57.210
11.82


1738
PRO
CG
58.892
29.277
57.324
12.42


1739
PRO
CD
58.963
28.340
58.496
11.92


1740
VAL
N
54.674
27.911
56.610
12.70


1741
VAL
CA
53.984
27.163
55.557
12.91


1742
VAL
C
54.744
27.391
54.248
13.19


1743
VAL
O
55.220
28.484
53.926
11.64


1744
VAL
CB
52.499
27.578
55.507
13.06


1745
VAL
CG1
51.592
26.621
54.745
14.25


1746
VAL
CG2
52.321
28.992
54.937
13.39


1747
VAL
N
54.874
26.281
53.520
12.59


1748
VAL
CA
55.295
26.380
52.106
11.98


1749
VAL
C
54.101
26.584
51.157
12.38


1750
VAL
O
53.183
25.771
51.097
15.24


1751
VAL
CB
56.061
25.107
51.706
9.51


1752
VAL
CG1
57.319
24.946
52.599
9.49


1753
VAL
CG2
56.454
25.144
50.213
10.06


1754
VAL
N
54.126
27.689
50.434
10.51


1755
VAL
CA
53.077
27.963
49.445
10.15


1756
VAL
C
53.712
27.938
48.046
11.07


1757
VAL
O
54.761
28.530
47.785
11.12


1758
VAL
CB
52.435
29.351
49.698
9.24


1759
VAL
CG1
51.958
29.592
51.143
8.57


1760
VAL
CG2
51.325
29.657
48.689
9.28


1761
HIS
N
53.032
27.235
47.133
10.38


1762
HIS
CA
53.504
27.236
45.747
8.48


1763
HIS
C
52.373
27.222
44.762
10.06


1764
HIS
O
51.254
26.782
45.047
9.96


1765
HIS
CB
54.558
26.153
45.458
8.91


1766
HIS
CG
53.991
24.769
45.162
8.64


1767
HIS
ND1
53.572
24.395
43.919
7.44


1768
HIS
CD2
53.803
23.723
46.048
8.51


1769
HIS
CE1
53.098
23.130
43.981
9.19


1770
HIS
NE2
53.243
22.739
45.290
11.46


1771
CYS
N
52.695
27.766
43.579
10.31


1772
CYS
CA
51.889
27.543
42.384
8.62


1773
CYS
C
52.821
26.996
41.318
9.41


1774
CYS
O
53.697
26.240
41.661
9.11


1775
CYS
CB
51.158
28.783
41.966
9.94


1776
CYS
SG
52.104
30.295
42.054
10.94


1777
SER
N
52.652
27.373
40.056
9.15


1778
SER
CA
53.690
26.848
39.157
8.78


1779
SER
C
55.026
27.639
39.274
8.55


1780
SER
O
56.127
27.100
39.390
8.15


1781
SER
CB
53.108
26.847
37.734
7.93


1782
SER
OG
54.103
26.437
36.830
8.26


1783
ALA
N
54.879
28.997
39.335
8.61


1784
ALA
CA
56.088
29.824
39.571
7.66


1785
ALA
C
56.362
30.302
41.022
8.82


1786
ALA
O
57.443
30.767
41.388
11.75


1787
ALA
CB
55.994
31.024
38.665
7.00


1788
GLY
N
55.332
30.135
41.872
8.66


1789
GLY
CA
55.504
30.616
43.255
8.32


1790
GLY
C
55.306
32.127
43.454
9.76


1791
GLY
O
55.810
32.695
44.413
10.12


1792
ILE
N
54.593
32.756
42.493
11.14


1793
ILE
CA
54.394
34.217
42.519
12.07


1794
ILE
C
52.948
34.722
42.312
10.76


1795
ILE
O
52.428
35.499
43.094
12.85


1796
ILE
CB
55.434
34.998
41.644
8.68


1797
ILE
CG1
55.274
34.717
40.134
9.17


1798
ILE
CG2
56.862
34.670
42.093
8.98


1799
ILE
CD1
56.328
35.365
39.216
7.46


1800
GLY
N
52.269
34.172
41.269
10.38


1801
GLY
CA
50.932
34.709
40.970
9.10


1802
GLY
C
49.783
34.383
41.944
10.90


1803
GLY
O
49.349
35.185
42.763
10.20


1804
ARG
N
49.366
33.089
41.810
11.01


1805
ARG
CA
48.418
32.462
42.759
10.63


1806
ARG
C
48.954
32.468
44.215
10.18


1807
ARG
O
48.254
32.844
45.134
10.97


1808
ARG
CB
48.025
31.034
42.275
9.12


1809
ARG
CG
47.247
31.120
40.967
9.78


1810
ARG
CD
47.007
29.785
40.293
7.58


1811
ARG
NE
48.188
29.323
39.636
8.89


1812
ARG
CZ
48.221
28.218
38.919
9.55


1813
ARG
NH1
47.173
27.474
38.805
10.16


1814
ARG
NH2
49.286
27.911
38.225
9.68


1815
SER
N
50.258
32.092
44.358
10.07


1816
SER
CA
50.854
32.120
45.724
8.26


1817
SER
C
50.864
33.513
46.362
10.19


1818
SER
O
50.529
33.638
47.522
10.34


1819
SER
CB
52.294
31.691
45.717
8.89


1820
SER
OG
52.445
30.336
45.240
11.05


1821
GLY
N
51.192
34.586
45.584
10.44


1822
GLY
CA
51.137
35.968
46.103
8.60


1823
GLY
C
49.743
36.409
46.483
9.62


1824
GLY
O
49.523
37.100
47.455
11.83


1825
THR
N
48.755
35.971
45.676
11.37


1826
THR
CA
47.324
36.271
45.940
10.02


1827
THR
C
46.841
35.647
47.237
11.10


1828
THR
O
46.328
36.337
48.121
9.82


1829
THR
CB
46.392
35.796
44.796
9.53


1830
THR
OG1
46.832
36.337
43.530
10.14


1831
THR
CG2
44.927
36.128
45.095
8.73


1832
PHE
N
47.096
34.326
47.377
9.10


1833
PHE
CA
46.838
33.635
48.636
10.60


1834
PHE
C
47.384
34.332
49.931
10.58


1835
PHE
O
46.702
34.625
50.911
11.24


1836
PHE
CB
47.311
32.168
48.478
8.88


1837
PHE
CG
47.118
31.324
49.741
9.58


1838
PHE
CD1
45.907
30.608
49.935
11.54


1839
PHE
CD2
48.151
31.261
50.713
11.23


1840
PHE
CE1
45.741
29.809
51.090
6.44


1841
PHE
CE2
47.985
30.464
51.879
9.94


1842
PHE
CZ
46.787
29.741
52.023
6.47


1843
CYS
N
48.703
34.583
49.832
10.70


1844
CYS
CA
49.413
35.190
50.962
10.02


1845
CYS
C
49.027
36.625
51.272
10.89


1846
CYS
O
48.945
37.006
52.423
12.32


1847
CYS
CB
50.929
35.091
50.816
12.17


1848
CYS
SG
51.574
33.397
50.718
15.41


1849
LEU
N
48.766
37.424
50.215
10.01


1850
LEU
CA
48.287
38.785
50.451
10.37


1851
LEU
C
46.994
38.815
51.257
10.12


1852
LEU
O
46.890
39.510
52.246
9.30


1853
LEU
CB
48.149
39.524
49.125
9.12


1854
LEU
CG
47.758
40.996
49.225
11.23


1855
LEU
OD1
47.427
41.612
47.834
11.32


1856
LEU
CD2
48.778
41.823
50.020
11.96


1857
ALA
N
46.015
37.982
50.789
10.91


1858
ALA
CA
44.724
37.906
51.492
10.80


1859
ALA
C
44.906
37.426
52.955
11.33


1860
ALA
O
44.454
38.026
53.923
10.76


1861
ALA
CB
43.764
36.998
50.732
7.83


1862
ASP
N
45.678
36.373
53.117
11.75


1863
ASP
CA
45.996
35.908
54.497
11.91


1864
ASP
C
46.600
36.952
55.469
11.55


1865
ASP
O
46.156
37.208
56.590
11.95


1866
ASP
CB
46.840
34.628
54.482
10.16


1867
ASP
CG
46.956
34.094
55.912
13.48


1868
ASP
OD1
45.954
33.856
56.609
12.31


1869
ASP
OD2
48.073
33.934
56.360
12.63


1870
THR
N
47.625
37.598
54.924
10.97


1871
THR
CA
48.347
38.561
55.751
11.02


1872
THR
C
47.504
39.800
55.982
11.79


1873
THR
O
47.502
40.323
57.088
11.99


1874
THR
CB
49.692
39.040
55.137
11.07


1875
THR
OG1
50.625
37.985
55.158
11.80


1876
THR
CG2
50.336
40.218
55.881
10.36


1877
CYS
N
46.764
40.247
54.943
10.65


1878
CYS
CA
45.827
41.365
55.230
10.63


1879
CYS
C
44.740
41.106
56.320
12.96


1880
CYS
O
44.486
41.919
57.205
13.56


1881
CYS
CB
45.123
41.924
53.999
10.48


1882
CYS
SG
46.329
42.755
52.937
13.42


1883
LEU
N
44.189
39.878
56.268
10.64


1884
LEU
CA
43.255
39.449
57.316
11.23


1885
LEU
C
43.865
39.322
58.731
12.65


1886
LEU
O
43.280
39.757
59.707
14.44


1887
LEU
CB
42.560
38.133
56.873
9.49


1888
LEU
CG
41.665
38.328
55.653
8.57


1889
LEU
CD1
40.477
39.186
55.978
10.68


1890
LEU
CD2
41.173
37.002
55.114
11.48


1891
LEU
N
45.089
38.753
58.780
13.24


1892
LEU
CA
45.873
38.751
60.039
12.90


1893
LEU
C
46.154
40.116
60.664
13.36


1894
LEU
O
45.961
40.401
61.827
15.00


1895
LEU
CB
47.209
38.118
59.142
12.90


1896
LEU
CG
47.717
37.083
60.724
17.31


1897
LEU
CD1
47.104
37.072
62.115
17.90


1898
LEU
CD2
49.240
37.021
60.648
17.91


1899
LEU
N
46.613
41.024
59.811
14.06


1900
LEU
CA
46.725
42.436
60.177
15.83


1901
LEU
C
45.461
43.107
60.760
15.86


1902
LEU
O
45.460
43.682
61.849
15.48


1903
LEU
CB
47.201
43.234
58.964
15.91


1904
LEU
CG
48.624
43.774
58.904
18.29


1905
LEU
CD1
49.052
43.573
57.469
20.36


1906
LEU
CD2
49.641
43.305
59.923
16.23


1907
MET
N
44.375
42.978
59.989
14.06


1908
MET
CA
43.106
43.427
60.510
16.10


1909
MET
C
42.674
42.850
61.894
18.37


1910
MET
O
42.126
43.531
62.759
17.82


1911
MET
CB
42.118
43.137
59.401
17.90


1912
MET
CG
40.713
43.550
59.741
22.88


1913
MET
SD
39.601
43.214
58.369
27.93


1914
MET
CE
40.671
43.783
57.014
21.01


1915
ASP
N
42.996
41.548
62.049
17.66


1916
ASP
CA
42.752
40.766
63.290
18.72


1917
ASP
C
43.468
41.301
64.551
20.72


1918
ASP
O
42.988
41.449
65.670
18.46


1919
ASP
CB
43.151
39.310
62.959
15.77


1920
ASP
CG
42.280
38.294
63.654
15.78


1921
ASP
OD1
41.335
38.723
64.270
15.30


1922
ASP
OD2
42.563
37.090
63.595
12.03


1923
LYS
N
44.725
41.679
64.309
22.67


1924
LYS
CA
45.442
42.083
65.515
26.79


1925
LYS
C
45.030
43.365
66.118
27.91


1926
LYS
O
45.173
43.640
67.292
27.25


1927
LYS
CB
46.939
42.117
65.368
31.63


1928
LYS
CG
47.623
43.011
64.367
36.21


1929
LYS
CD
49.088
42.561
64.344
41.15


1930
LYS
CE
49.122
41.080
63.907
45.83


1931
LYS
NZ
49.950
40.195
64.789
48.52


1932
ARG
N
44.496
44.183
65.244
29.18


1933
ARG
CA
44.107
45.458
65.814
30.25


1934
ARG
C
42.610
45.701
65.816
28.51


1935
ARG
O
42.101
46.694
66.298
29.83


1936
ARG
CB
44.909
46.490
65.022
35.96


1937
ARG
CG
44.730
46.304
63.509
35.60


1938
ARG
CD
45.670
47.261
62.794
39.72


1939
ARG
NE
47.048
46.827
62.880
44.72


1940
ARG
CZ
47.922
47.107
61.918
49.49


1941
ARG
NH1
47.618
47.655
60.744
46.55


1942
ARG
NH2
49.174
46.847
62.219
54.27


1943
LYS
N
41.920
44.731
65.188
24.03


1944
LYS
CA
40.522
44.893
64.863
22.66


1945
LYS
C
40.206
46.220
64.139
22.19


1946
LYS
O
39.223
46.916
64.337
22.54


1947
LYS
CB
39.649
44.455
66.104
23.45


1948
LYS
CG
39.743
42.957
66.570
20.10


1949
LYS
CD
39.208
41.813
65.634
20.71


1950
LYS
CE
39.159
40.316
66.166
17.94


1951
LYS
NZ
38.787
39.163
65.278
27.72


1952
ASP
N
41.140
46.551
63.222
21.48


1953
ASP
CA
41.082
47.870
62.548
22.85


1954
ASP
C
41.316
47.877
61.015
21.41


1955
ASP
O
42.375
48.119
60.444
21.48


1956
ASP
CB
41.986
48.893
63.285
25.58


1957
ASP
CG
41.991
50.280
62.654
29.64


1958
ASP
OD1
41.113
50.584
61.818
31.77


1959
ASP
OD2
42.919
51.024
62.980
30.41


1960
PRO
N
40.247
47.578
60.311
20.58


1961
PRO
CA
40.371
47.322
58.886
22.04


1962
PRO
C
40.829
48.515
58.129
24.22


1963
PRO
O
41.512
48.463
57.118
22.77


1964
PRO
CB
38.944
47.032
58.454
23.82


1965
PRO
CG
38.145
46.699
59.709
22.76


1966
PRO
CD
38.893
47.416
60.819
22.17


1967
SER
N
40.411
49.657
58.676
26.49


1968
SER
CA
40.771
50.891
57.983
29.21


1969
SER
C
42.244
51.221
58.015
28.16


1970
SER
O
42.769
51.948
57.184
30.98


1971
SER
CB
39.918
52.100
58.446
32.36


1972
SER
OG
38.686
52.172
57.658
37.57


1973
SER
N
42.922
50.561
58.956
25.94


1974
SER
CA
44.384
50.605
58.947
23.97


1975
SER
C
45.142
49.677
58.018
23.07


1976
SER
O
46.361
49.640
58.035
23.41


1977
SER
CB
44.987
50.283
60.317
24.53


1978
SER
OG
44.902
48.866
60.519
26.18


1979
VAL
N
44.421
48.864
57.246
22.45


1980
VAL
CA
45.137
48.031
56.270
21.20


1981
VAL
C
45.123
48.557
54.850
21.26


1982
VAL
O
44.092
48.802
54.231
22.49


1983
VAL
CB
45.002
46.493
56.466
22.58


1984
VAL
CG1
44.884
45.658
55.190
20.76


1985
VAL
CG2
44.174
46.080
57.682
17.17


1986
ASP
N
46.355
48.833
54.405
19.92


1987
ASP
CA
46.605
49.285
53.043
19.98


1988
ASP
C
47.081
48.123
52.164
17.61


1989
ASP
O
48.232
47.702
52.203
18.51


1990
ASP
CB
47.639
50.404
53.178
21.39


1991
ASP
CG
47.956
51.130
51.885
25.31


1992
ASP
OD1
47.820
50.542
50.821
23.58


1993
ASP
OD2
48.409
52.287
51.944
32.08


1994
ILE
N
46.134
47.556
51.413
18.00


1995
ILE
CA
46.483
46.335
50.680
16.17


1996
ILE
C
47.626
46.519
49.725
16.20


1997
ILE
O
48.485
45.657
49.701
16.71


1998
ILE
CB
45.244
45.758
49.959
18.69


1999
ILE
CG1
44.185
45.428
51.013
20.07


2000
ILE
CG2
45.559
44.493
49.137
16.13


2001
ILE
CD1
42.889
44.877
50.407
22.35


2002
LYS
N
47.646
47.644
48.951
15.61


2003
LYS
CA
48.796
47.807
48.039
16.12


2004
LYS
C
50.135
47.931
48.716
15.62


2005
LYS
O
51.153
47.394
48.321
15.12


2006
LYS
CB
48.689
49.055
47.235
18.84


2007
LYS
CG
47.447
49.010
46.334
31.31


2008
LYS
CD
47.091
50.385
45.684
37.73


2009
LYS
CE
47.284
51.463
46.766
43.40


2010
LYS
NZ
46.243
52.480
46.893
47.06


2011
LYS
N
50.099
48.648
49.820
16.19


2012
LYS
CA
51.282
48.662
50.657
17.17


2013
LYS
C
51.745
47.323
51.261
15.81


2014
LYS
O
52.929
47.020
51.262
13.38


2015
LYS
CB
51.004
49.698
51.724
21.47


2016
LYS
CG
52.262
50.268
52.260
26.41


2017
LYS
CD
52.080
51.628
52.944
32.75


2018
LYS
CE
51.717
52.861
52.072
37.01


2019
LYS
NZ
52.068
54.091
52.860
41.44


2020
VAL
N
50.779
46.493
51.746
15.38


2021
VAL
CA
51.243
45.153
52.147
13.40


2022
VAL
C
51.721
44.256
51.029
12.42


2023
VAL
O
52.682
43.538
51.174
12.19


2024
VAL
CB
50.424
44.394
53.259
17.62


2025
VAL
CG1
50.125
42.920
53.057
13.70


2026
VAL
CG2
49.369
45.253
53.949
14.26


2027
LEU
N
51.133
44.416
49.870
11.53


2028
LEU
CA
51.731
43.742
48.691
12.42


2029
LEU
C
53.154
44.176
48.316
11.91


2030
LEU
O
54.046
43.392
48.055
10.65


2031
LEU
CB
50.805
4a.927
47.497
12.94


2032
LEU
CG
51.267
43.151
46.270
14.51


2033
LEU
CD1
50.310
43.372
45.083
14.86


2034
LEU
CD2
51.468
41.649
46.603
12.64


2035
LEU
N
53.356
45.507
48.366
14.10


2036
LEU
CA
54.728
46.026
48.214
13.57


2037
LEU
C
55.705
45.555
49.289
11.98


2038
LEU
O
56.801
45.159
48.950
10.15


2039
LEU
CB
54.659
47.567
48.096
15.92


2040
LEU
CG
54.751
48.229
46.702
18.96


2041
LEU
CD1
53.794
49.403
46.600
18.76


2042
LEU
CD2
54.861
47.323
45.482
20.15


2043
ASP
N
55.280
45.511
50.587
13.06


2044
ASP
CA
56.110
44.828
51.584
12.70


2045
ASP
C
56.460
43.385
51.230
11.44


2046
ASP
O
57.602
42.960
51.239
11.16


2047
ASP
CB
55.726
44.946
53.135
15.05


2048
ASP
CG
57.045
45.344
53.997
23.08


2049
ASP
OD1
57.469
46.507
54.030
22.88


2050
ASP
OD2
57.754
44.542
54.624
24.92


2051
MET
N
55.430
42.623
50.818
13.08


2052
MET
CA
55.755
41.284
50.344
12.59


2053
MET
C
56.726
41.161
49.161
10.76


2054
MET
O
57.544
40.258
49.155
9.86


2055
MET
CB
54.494
40.507
49.955
14.18


2056
MET
CG
53.772
39.803
51.043
20.95


2057
MET
SD
52.297
39.007
50.399
25.25


2058
MET
CE
51.819
38.502
52.033
24.15


2059
ARG
N
56.616
42.061
48.195
11.81


2060
ARG
CA
57.544
42.017
47.025
14.09


2061
ARG
C
59.018
42.435
47.298
14.19


2062
ARG
O
59.958
42.214
46.558
15.37


2063
ARG
CB
57.006
42.765
45.786
15.27


2064
ARG
CG
55.506
42.740
45.458
20.41


2065
ARG
CD
54.800
42.082
44.276
22.57


2066
ARG
NE
55.067
42.731
43.066
21.00


2067
ARG
CZ
54.603
42.591
41.803
19.36


2068
ARG
NH1
53.481
42.040
41.379
17.30


2069
ARG
NH2
55.419
43.076
40.926
15.47


2070
LYS
N
59.216
42.912
48.567
12.82


2071
LYS
CA
60.619
42.962
49.027
11.88


2072
LYS
C
61.320
41.630
49.166
11.52


2073
LYS
O
62.519
41.494
49.116
12.87


2074
LYS
CB
60.733
43.761
50.344
10.90


2075
LYS
CG
60.143
45.169
50.220
10.61


2076
LYS
CD
60.078
45.786
51.630
16.89


2077
LYS
CE
59.704
47.286
51.748
18.25


2078
LYS
NZ
59.840
47.665
53.175
18.64


2079
PHE
N
60.530
40.573
49.403
11.46


2080
PHE
CA
61.062
39.240
49.651
10.66


2081
PHE
C
60.961
38.264
48.481
10.63


2082
PHE
O
61.718
37.304
48.372
11.08


2083
PHE
CB
60.312
38.582
50.824
10.87


2084
PHE
CG
60.347
39.458
52.036
10.74


2085
PHE
CD1
61.470
39.374
52.899
14.67


2086
PHE
CD2
59.277
40.336
52.321
13.16


2087
PHE
CE1
61.505
40.174
54.080
14.61


2088
PHE
CE2
59.312
41.139
53.481
11.84


2089
PHE
CZ
60.439
41.068
54.334
12.78


2090
ARG
N
59.991
38.503
47.589
11.78


2091
ARG
CA
60.048
37.752
46.323
11.12


2092
ARG
C
59.438
38.615
45.199
10.70


2093
ARG
O
58.427
39.277
45.416
11.00


2094
ARG
CB
59.361
36.360
46.491
9.05


2095
ARG
CG
59.547
35.389
45.310
8.54


2096
ARG
CD
58.829
34.077
45.618
8.35


2097
ARG
NE
58.807
33.096
44.485
8.45


2098
ARG
CZ
59.812
32.305
44.135
8.44


2099
ARG
NH1
60.967
32.419
44.711
8.74


2100
ARG
NH2
59.670
31.395
43.187
9.54


2101
MET
N
60.064
38.542
43.986
11.10


2102
MET
CA
59.514
39.256
42.833
10.52


2103
MET
C
58.123
38.755
42.342
12.21


2104
MET
O
57.716
37.596
42.401
11.69


2105
MET
CB
60.515
39.57
41.664
12.40


2106
MET
CG
60.688
37.693
41.161
13.12


2107
MET
SD
61.708
37.587
39.673
12.49


2108
MET
CE
63.258
38.266
40.330
14.52


2109
GLY
N
57.384
39.697
41.822
11.82


2110
GLY
CA
56.244
39.387
40.947
10.69


2111
GLY
C
55.014
38.778
41.578
11.80


2112
GLY
O
54.118
38.340
40.868
11.81


2113
LEU
N
54.995
38.855
42.924
11.43


2114
LEU
CA
53.802
38.497
43.681
11.39


2115
LEU
C
52.518
39.174
43.279
12.20


2116
LEU
O
52.384
40.390
43.261
12.24


2117
LEU
CB
54.050
38.674
45.197
10.83


2118
LEU
CG
55.281
37.955
45.738
9.47


2119
LEU
CD1
55.323
36.465
45.320
9.16


2120
LEU
CD2
55.336
38.148
47.254
10.38


2121
ILE
N
51.588
38.296
42.897
10.54


2122
ILE
CA
50.396
38.717
42.153
11.17


2123
ILE
C
50.699
39.082
40.678
13.75


2124
ILE
O
51.436
40.016
40.396
13.91


2125
ILE
CB
49.557
39.790
42.868
11.11


2126
ILE
CG1
49.177
39.212
44.233
9.13


2127
ILE
CG2
48.312
40.138
42.008
14.38


2128
ILE
CD1
48.073
39.967
44.918
8.65


2129
GLN
N
50.157
38.291
39.721
13.18


2130
GLN
CA
50.662
38.385
38.342
12.31


2131
GLN
C
49.766
39.112
37.360
14.51


2132
GLN
O
50.188
39.490
36.276
14.93


2133
GLN
CB
51.037
36.985
37.828
12.10


2134
GLN
CG
52.401
36.558
38.336
13.08


2135
GLN
CD
53.427
37.182
37.460
14.33


2136
GLN
OE1
53.477
36.854
36.292
16.45


2137
GLN
NE2
54.248
38.058
38.029
11.97


2138
THR
N
48.519
39.356
37.823
14.47


2139
THR
CA
47.567
40.130
37.057
13.82


2140
THR
C
46.787
41.158
37.866
15.31


2141
THR
O
46.656
41.081
39.092
15.21


2142
THR
CB
46.554
39.229
36.350
12.44


2143
THR
OG1
45.588
38.765
37.287
13.84


2144
THR
CG2
47.152
38.042
35.581
12.80


2145
ALA
N
46.231
42.152
37.125
16.12


2146
ALA
CA
45.346
43.159
37.762
17.15


2147
ALA
C
44.035
42.573
38.343
17.06


2148
ALA
O
43.495
43.018
39.351
16.84


2149
ALA
CB
44.987
44.299
36.780
15.40


2150
ASP
N
43.567
41.485
37.685
16.67


2151
ASP
CA
42.388
40.777
38.209
16.05


2152
ASP
C
42.651
39.978
39.460
14.16


2153
ASP
O
41.818
39.960
40.360
13.25


2154
ASP
CB
41.797
39.833
37.180
16.36


2155
ASP
CG
40.336
39.658
37.485
18.91


2156
ASP
OD1
39.640
40.638
37.769
19.27


2157
ASP
OD2
39.876
38.522
37.453
19.47


2158
GLN
N
43.857
39.397
39.542
12.74


2159
GLN
CA
44.257
38.815
40.853
12.47


2160
GLN
C
44.351
39.857
41.984
13.42


2161
GLN
O
43.906
39.646
43.101
13.68


2162
GLN
CB
45.579
38.040
40.754
10.94


2163
GLN
CG
45.467
36.777
39.876
10.93


2164
GLN
CD
46.795
36.101
39.634
11.89


2165
GLN
OE1
47.863
36.660
39.815
13.27


2166
GLN
NE2
46.739
34.859
39.129
10.17


2167
LEU
N
44.892
41.066
41.654
15.21


2168
LEU
CA
44.818
42.209
42.611
13.64


2169
LEU
C
43.408
42.567
43.025
14.41


2170
LEU
O
43.078
42.676
44.201
15.65


2171
LEU
CB
45.560
43.441
42.074
12.86


2172
LEU
CG
45.681
44.598
43.045
13.02


2173
LEU
CD1
46.174
45.889
42.389
12.87


2174
LEU
CD2
46.540
44.205
44.235
12.32


2175
ARG
N
42.543
42.691
41.995
13.43


2176
ARG
CA
41.161
42.989
42.303
13.38


2177
ARG
C
40.433
41.964
43.135
14.16


2178
ARG
O
39.716
42.292
44.066
14.64


2179
ARG
CB
40.407
43.216
41.022
13.46


2180
ARG
CG
38.925
43.525
41.286
13.29


2181
ARG
CD
38.171
43.714
39.976
16.52


2182
ARG
NE
36.823
44.228
40.247
20.17


2183
ARG
CZ
35.772
43.485
40.354
19.49


2184
ARG
NH1
35.807
42.186
40.332
20.88


2185
ARG
NH2
34.650
44.103
40.484
21.32


2186
PHE
N
40.683
40.692
42.778
13.41


2187
PHE
CA
40.279
39.551
43.612
13.00


2188
PHE
C
40.781
39.564
45.054
12.42


2189
PHE
O
40.006
39.259
45.937
14.84


2190
PHE
CB
40.652
38.200
42.969
12.87


2191
PHE
CG
40.024
37.029
43.724
13.08


2192
PHE
CD1
38.719
36.588
43.410
15.82


2193
PHE
CD2
40.732
36.435
44.792
13.48


2194
PHE
CE1
38.069
35.621
44.224
14.88


2195
PHE
CE2
40.074
35.497
45.610
14.71


2196
PHE
CZ
38.737
35.123
45.347
13.48


2197
SER
N
42.069
39.939
45.279
12.86


2198
SER
CA
42.661
40.146
46.627
13.82


2199
SER
C
41.892
41.095
47.511
15.06


2200
SER
O
41.566
40.755
48.633
15.36


2201
SER
CB
44.037
40.790
46.596
11.50


2202
SER
OG
44.867
39.808
46.005
19.07


2203
TYR
N
41.541
42.275
46.959
14.37


2204
TYR
CA
40.568
43.166
47.642
13.98


2205
TYR
C
39.191
42.565
47.958
14.72


2206
TYR
O
38.720
42.678
49.061
16.92


2207
TYR
CB
40.237
44.390
46.809
15.56


2208
TYR
CG
41.257
45.499
46.833
15.10


2209
TYR
CD1
42.504
45.344
46.171
15.01


2210
TYR
CD2
40.898
46.710
47.477
16.69


2211
TYR
CE1
43.433
46.405
46.232
17.26


2212
TYR
CE2
41.786
47.793
47.473
17.79


2213
TYR
CZ
43.052
47.618
46.872
18.91


2214
TYR
OH
43.970
48.651
46.941
22.03


2215
LEU
N
38.561
41.892
46.996
14.60


2216
LEU
CA
37.297
41.190
47.263
13.80


2217
LEU
C
37.350
40.153
48.419
13.84


2218
LEU
O
36.585
40.029
49.351
15.22


2219
LEU
CB
36.998
40.456
45.966
15.22


2220
LEU
CG
35.889
40.943
45.032
17.91


2221
LEU
CD1
36.181
40.536
43.608
17.36


2222
LEU
CD2
35.469
42.386
45.200
17.38


2223
ALA
N
38.419
39.344
48.343
13.18


2224
ALA
CA
38.629
38.360
49.433
12.65


2225
ALA
C
38.897
38.956
50.826
14.16


2226
ALA
O
38.371
38.463
51.807
14.00


2227
ALA
CB
39.768
37.370
49.099
13.02


2228
VAL
N
39.721
40.035
50.884
11.78


2229
VAL
CA
39.918
40.769
52.138
12.53


2230
VAL
C
38.651
41.510
52.651
13.82


2231
VAL
O
38.291
41.427
53.828
12.86


2232
VAL
CB
41.111
41.728
52.070
11.66


2233
VAL
CG1
42.380
40.915
51.747
13.24


2234
VAL
CG2
41.316
42.491
53.376
9.92


2235
ILE
N
37.962
42.204
51.727
12.29


2236
ILE
CA
36.692
42.836
52.151
13.94


2237
ILE
C
35.643
41.821
52.683
14.15


2238
ILE
O
35.051
42.017
53.733
14.06


2239
ILE
CB
36.150
43.725
50.998
13.50


2240
ILE
CG1
37.132
44.878
50.705
14.91


2241
ILE
CG2
34.736
44.246
51.344
12.74


2242
ILE
CD1
36.837
45.561
49.370
13.99


2243
GLU
N
35.524
40.682
51.982
13.27


2244
GLU
CA
34.623
39.640
52.511
12.79


2245
GLU
C
35.054
38.960
53.810
14.22


2246
GLU
O
34.348
38.838
54.812
14.98


2247
GLU
CB
34.469
38.619
51.428
11.88


2248
GLU
CG
33.577
37.436
51.758
12.69


2249
GLU
CD
32.144
37.802
52.097
18.61


2250
GLU
OE1
31.662
38.871
51.750
19.68


2251
GLU
OE2
31.437
37.016
52.719
20.07


2252
GLY
N
36.351
38.579
53.807
14.10


2253
GLY
CA
36.996
38.012
55.024
11.35


2254
GLY
C
36.903
38.905
56.279
12.42


2255
GLY
O
36.792
38.436
57.408
14.09


2256
ALA
N
36.936
40.244
56.035
12.11


2257
ALA
CA
36.786
41.194
57.129
13.24


2258
ALA
C
35.555
40.936
57.966
14.50


2259
ALA
O
35.567
41.104
59.163
15.74


2260
ALA
CB
36.717
42.628
56.649
12.85


2261
LYS
N
34.522
40.415
57.318
15.43


2262
LYS
CA
33.316
40.077
58.087
17.97


2263
LYS
C
33.511
39.126
59.305
18.17


2264
LYS
O
33.007
39.309
60.412
16.72


2265
LYS
CB
32.232
39.479
57.184
17.36


2266
LYS
CG
31.843
40.457
56.080
20.89


2267
LYS
CD
30.798
39.777
55.206
19.35


2268
LYS
CE
30.249
40.618
54.078
21.45


2269
LYS
NZ
29.750
39.613
53.147
28.58


2270
PHE
N
34.298
38.096
58.987
17.06


2271
PHE
CA
34.710
37.136
60.018
17.26


2272
PHE
C
35.681
37.783
61.042
17.65


2273
PHE
O
35.418
37.750
62.227
17.35


2274
PHE
CB
35.243
35.871
59.313
16.04


2275
PHE
CG
35.710
34.853
60.327
18.17


2276
PHE
CD1
36.999
34.982
60.906
18.77


2277
PHE
CD2
34.842
33.806
60.681
17.46


2278
PHE
CE1
37.423
34.059
61.897
18.56


2279
PHE
CE2
35.280
32.867
61.642
17.26


2280
PHE
CZ
36.551
33.006
62.234
16.76


2281
ILE
N
36.741
38.443
60.524
17.16


2282
ILE
CA
37.667
39.052
61.474
16.95


2283
ILE
C
36.960
40.030
62.419
18.22


2284
ILE
O
37.307
40.294
63.547
19.58


2285
ILE
CB
38.752
39.831
60.687
16.65


2286
ILE
CG1
39.499
39.025
59.668
15.20


2287
ILE
CG2
39.745
40.510
61.608
17.33


2288
ILE
CD1
40.138
37.768
60.180
16.00


2289
MET
N
35.924
40.676
61.869
17.76


2290
MET
CA
35.293
41.696
62.708
17.15


2291
MET
C
34.125
41.213
63.554
18.59


2292
MET
O
33.271
42.006
63.936
18.92


2293
MET
CB
34.850
42.902
61.856
18.33


2294
MET
CG
36.096
43.579
61.237
18.10


2295
MET
SD
37.293
44.167
62.479
22.98


2296
MET
CE
36.332
45.615
62.928
22.14


2297
GLY
N
34.097
39.878
63.787
17.81


2298
GLY
CA
33.117
39.341
64.764
19.24


2299
GLY
C
31.932
38.467
64.303
18.12


2300
GLY
O
31.162
37.852
65.052
18.31


2301
ASP
N
31.751
38.493
62.977
16.53


2302
ASP
CA
30.662
37.671
62.462
17.00


2303
ASP
C
31.116
36.272
62.108
18.13


2304
ASP
O
31.346
35.891
60.957
19.06


2305
ASP
CB
29.981
38.377
61.275
18.82


2306
ASP
CG
28.755
37.606
60.749
20.22


2307
ASP
OD1
28.315
36.651
61.382
19.51


2308
ASP
OD2
28.234
37.955
59.688
23.56


2309
SER
N
31.276
35.460
63.182
18.73


2310
SER
CA
31.804
34.126
62.883
16.96


2311
SER
C
30.962
33.233
61.948
18.39


2312
SER
O
31.432
32.300
61.284
18.33


2313
SER
CB
32.076
33.353
64.164
17.13


2314
SER
OG
33.211
33.889
64.866
14.25


2315
SER
N
29.647
33.584
61.904
17.50


2316
SER
CA
28.726
32.804
61.055
18.74


2317
SER
C
28.994
32.849
59.528
17.75


2318
SER
O
28.665
31.927
58.776
16.68


2319
SER
CB
27.259
33.169
61.335
19.67


2320
SER
OG
26.885
34.432
60.758
21.88


2321
VAL
N
29.690
33.918
59.107
17.27


2322
VAL
CA
30.098
33.858
57.707
18.22


2323
VAL
C
30.893
32.658
57.299
18.73


2324
VAL
O
30.749
32.254
56.163
19.63


2325
VAL
CB
30.851
35.081
57.155
20.69


2326
VAL
CG1
32.145
35.419
57.906
17.79


2327
VAL
CG2
29.886
36.225
56.907
23.70


2328
GLN
N
31.676
32.100
58.244
18.28


2329
GLN
CA
32.498
30.973
57.851
19.78


2330
GLN
C
31.709
29.809
57.296
23.25


2331
GLN
O
31.866
29.325
56.194
25.12


2332
GLN
CB
33.350
30.549
59.027
20.56


2333
GLN
CG
34.279
29.396
58.650
24.84


2334
GLN
CD
35.223
29.031
59.768
27.26


2335
GLN
OE1
35.456
29.725
60.745
31.04


2336
GLN
NE2
35.798
27.883
59.602
29.42


2337
ASP
N
30.649
29.485
58.075
25.31


2338
ASP
CA
29.810
28.447
57.454
27.02


2339
ASP
C
28.987
28.769
56.202
25.79


2340
ASP
O
28.680
27.943
55.345
25.32


2341
ASP
CB
29.058
27.677
58.540
35.78


2342
ASP
CG
30.060
26.695
59.218
44.92


2343
ASP
OD1
30.644
25.807
58.529
50.04


2344
ASP
OD2
30.268
26.816
60.445
50.59


2345
GLN
N
28.684
30.074
56.081
23.38


2346
GLN
CA
28.196
30.539
54.780
24.32


2347
GLN
C
29.105
30.389
53.573
23.16


2348
GLN
O
28.683
29.998
52.488
21.27


2349
GLN
CB
27.869
31.970
54.845
28.00


2350
GLN
CG
26.784
32.237
55.878
35.72


2351
GLN
CD
26.555
33.724
55.747
43.13


2352
GLN
OE1
26.549
34.281
54.641
48.57


2353
GLN
NE2
26.403
34.395
56.909
43.82


2354
TRP
N
30.382
30.678
53.819
20.29


2355
TRP
CA
31.346
30.362
52.750
19.31


2356
TRP
C
31.466
28.909
52.431
19.07


2357
TRP
O
31.450
28.527
51.271
19.20


2358
TRP
CB
32.784
30.779
53.114
19.26


2359
TRP
CG
32.909
32.243
53.480
15.65


2360
TRP
CD1
32.161
33.289
52.953
14.94


2361
TRP
CD2
33.865
32.827
54.394
15.85


2362
TRP
NE1
32.572
34.480
53.472
15.54


2363
TRP
CE2
33.623
34.245
54.377
15.86


2364
TRP
CE3
34.912
32.297
55.183
14.86


2365
TRP
CZ2
34.420
35.102
55.179
16.78


2366
TRP
CZ3
35.699
33.183
55.951
14.37


2367
TRP
CH2
35.460
34.572
55.969
15.56


2368
LYS
N
31.535
28.079
53.466
21.19


2369
LYS
CA
31.490
26.660
53.154
24.17


2370
LYS
C
30.299
26.154
52.302
25.28


2371
LYS
O
30.419
25.380
51.350
26.15


2372
LYS
CB
31.535
25.905
54.461
26.43


2373
LYS
CG
31.670
24.409
54.259
32.00


2374
LYS
CD
31.629
23.919
55.676
38.87


2375
LYS
CE
31.917
22.442
55.805
45.47


2376
LYS
NZ
31.660
22.084
57.228
51.74


2377
GLU
N
29.117
26.663
52.680
26.22


2378
GLU
CA
27.928
26.358
51.891
27.87


2379
GLU
C
27.975
26.877
50.455
26.53


2380
GLU
O
27.835
26.148
49.496
30.42


2381
GLU
CB
26.659
26.888
52.548
34.80


2382
GLU
CG
26.313
26.343
53.949
47.61


2383
GLU
CD
25.599
24.966
53.934
55.88


2384
GLU
OE1
24.348
24.925
53.838
59.76


2385
GLU
OE2
26.294
23.937
54.064
61.03


2386
LEU
N
28.258
28.163
50.302
24.19


2387
LEU
CA
28.499
28.736
48.972
23.43


2388
LEU
C
29.566
28.108
48.071
24.08


2389
LEU
O
29.553
28.130
46.848
22.85


2390
LEU
CB
29.014
30.112
49.163
25.02


2391
LEU
CG
27.980
31.163
49.085
25.39


2392
LEU
CD1
28.441
32.350
49.899
27.03


2393
LEU
CD2
26.614
30.675
49.478
28.40


2394
SER
N
30.563
27.564
48.762
23.22


2395
SER
CA
31.652
26.937
48.040
24.53


2396
SER
C
31.401
25.574
47.438
26.87


2397
SER
O
32.174
25.053
46.642
26.47


2398
SER
CB
32.858
26.864
48.941
23.92


2399
SER
OG
32.879
25.591
49.577
27.33


2400
HIS
N
30.272
24.958
47.865
29.80


2401
HIS
CA
29.907
23.613
47.358
33.13


2402
HIS
C
30.966
22.498
47.442
33.64


2403
HIS
O
31.210
21.764
46.489
31.30


2404
HIS
CB
29.302
23.669
45.909
36.51


2405
HIS
CG
28.204
24.708
45.783
40.71


2406
HIS
ND1
28.213
25.693
44.854
43.97


2407
HIS
CD2
27.063
24.893
46.600
42.68


2408
HIS
CE1
27.113
26.502
45.078
43.60


2409
HIS
NE2
26.408
26.006
46.157
42.67


2410
GLU
N
31.619
22.430
48.620
35.19


2411
GLU
CA
32.799
21.567
48.661
36.70


2412
GLU
C
32.611
20.063
48.720
38.60


2413
GLU
O
33.525
19.304
48.448
37.53


2414
GLU
CB
33.697
21.992
49.795
35.82


2415
GLU
CG
32.956
21.874
51.117
36.20


2416
GLU
CD
33.983
21.924
52.224
38.96


2417
GLU
OE1
34.913
22.725
52.123
36.60


2418
GLU
OE2
33.890
21.139
53.176
41.14


2419
ASP
N
31.402
19.658
49.089
42.63


2420
ASP
CA
31.156
18.226
49.154
46.40


2421
ASP
C
30.772
17.554
47.818
47.19


2422
ASP
O
30.066
18.144
46.977
46.38


2423
ASP
CB
30.260
17.938
50.394
50.98


2424
ASP
CG
31.161
17.875
51.659
57.85


2425
ASP
OD1
32.063
17.001
51.717
60.50


2426
ASP
OD2
30.999
18.696
52.591
61.02


2427
ASP
OXT
31.255
16.438
47.575
48.57


1
TIP3
OH2
60.719
23.664
43.966
20.00


2
TIP3
1H
60.985
23.573
44.873
20.00


3
TIP3
2H
60.658
24.587
43.766
20.00


4
TIP3
OH2
40.411
32.301
35.797
20.00


5
TIP3
1H
40.442
31.973
36.704
20.00


6
TIP3
2H
39.543
32.682
35.681
20.00


7
TIP3
OH2
45.842
40.160
69.804
20.00


8
TIP3
1H
46.390
40.196
70.592
20.00


9
TIP3
2H
46.479
40.472
69.181
20.00


10
TIP3
OH2
53.379
29.910
58.076
20.00


11
TIP3
1H
54.092
29.933
58.712
20.00


12
TIP3
2H
53.330
30.805
57.725
20.00


13
TIP3
OH2
65.665
24.233
43.388
20.00


14
TIP3
1H
66.318
23.787
43.947
20.00


15
TIP3
2H
66.089
25.124
43.306
20.00


16
TIP3
OH2
53.559
24.650
58.363
20.00


17
TIP3
1H
54.093
24.160
58.947
20.00


18
TIP3
2H
53.867
25.523
58.315
20.00


19
TIP3
OH2
64.454
48.312
45.244
20.00


20
TIP3
1H
64.267
48.158
46.175
20.00


21
TIP3
2H
63.857
49.038
45.064
20.00


22
TIP3
OH2
65.964
24.398
54.095
20.00


23
TIP3
1H
65.412
24.176
54.850
20.00


24
TIP3
2H
65.297
24.876
53.591
20.00


25
TIP3
OH2
45.682
25.930
65.899
20.00


26
TIP3
1H
46.136
26.039
66.729
20.00


27
TIP3
2H
45.378
26.840
65.851
20.00


28
TIP3
OH2
41.439
40.049
69.937
20.00


29
TIP3
1H
41.192
39.958
70.811
20.00


30
TIP3
2H
40.941
40.831
69.745
20.00


31
TIP3
OH2
44.346
6.948
53.731
20.00


32
TIP3
1H
44.331
7.414
54.574
20.00


33
TIP3
2H
43.897
7.661
53.211
20.00


34
TIP3
OH2
69.712
33.601
44.219
20.00


35
TIP3
1H
69.242
33.254
44.983
20.00


36
TIP3
2H
69.119
34.180
43.748
20.00


37
TIP3
OH2
58.068
40.012
37.522
20.00


38
TIP3
1H
57.605
39.244
37.688
20.00


39
TIP3
2H
57.929
40.200
36.598
20.00


40
TIP3
OH2
38.179
37.107
67.391
20.00


41
TIP3
1H
38.128
37.041
68.351
20.00


42
TIP3
2H
38.342
38.026
67.301
20.00


43
TIP3
OH2
53.580
42.001
38.764
20.00


44
TIP3
1H
53.963
41.667
39.579
20.00


45
TIP3
2H
53.329
42.839
39.103
20.00


46
TIP3
OH2
41.144
36.980
35.497
20.00


47
TIP3
1H
41.796
37.172
36.184
20.00


48
TIP3
2H
41.093
37.769
34.947
20.00


49
TIP3
OH2
63.542
14.613
42.941
20.00


50
TIP3
1H
63.904
14.292
43.762
20.00


51
TIP3
2H
63.730
15.559
42.948
20.00


52
TIP3
OH2
64.565
20.375
61.477
20.00


53
TIP3
1H
64.349
19.937
62.304
20.00


54
TIP3
2H
64.342
21.308
61.630
20.00


55
TIP3
OH2
73.801
37.858
38.356
20.00


56
TIP3
1H
73.658
37.517
39.241
20.00


57
TIP3
2H
73.755
38.813
38.502
20.00


58
TIP3
OH2
68.073
28.759
56.071
20.00


59
TIP3
1H
68.526
28.682
56.924
20.00


60
TIP3
2H
68.460
29.576
55.744
20.00


61
TIP3
OH2
66.813
32.500
36.292
20.00


62
TIP3
1H
66.619
33.294
36.779
20.00


63
TIP3
2H
67.059
32.915
35.452
20.00


64
TIP3
OH2
63.409
36.906
54.912
20.00


65
TIP3
1H
63.720
36.671
55.795
20.00


66
TIP3
2H
63.757
37.774
54.745
20.00


67
TIP3
OH2
75.979
37.116
45.918
20.00


68
TIP3
1H
75.933
36.923
46.791
20.00


69
TIP3
2H
75.587
37.969
45.865
20.00


70
TIP3
OH2
44.663
41.751
34.799
20.00


71
TIP3
1H
45.028
41.787
35.676
20.00


72
TIP3
2H
44.876
42.631
34.493
20.00


73
TIP3
OH2
26.251
25.219
59.180
20.00


74
TIP3
1H
26.739
25.004
59.969
20.00


75
TIP3
2H
26.454
26.133
58.987
20.00


76
TIP3
OH2
43.204
25.421
36.259
20.00


77
TIP3
1H
42.767
24.692
36.714
20.00


78
TIP3
2H
42.761
26.233
36.519
20.00


79
TIP3
OH2
48.443
47.491
57.210
20.00


80
TIP3
1H
48.360
47.421
58.167
20.00


81
TIP3
2H
48.503
48.418
56.985
20.00


82
TIP3
OH2
61.254
29.798
38.553
20.00


83
TIP3
1H
61.103
29.506
39.441
20.00


84
TIP3
2H
60.395
30.126
38.301
20.00


85
TIP3
OH2
76.145
33.804
35.273
20.00


86
TIP3
1H
76.871
33.620
35.878
20.00


87
TIP3
2H
76.462
34.565
34.787
20.00


88
TIP3
OH2
55.588
41.658
31.859
20.00


89
TIP3
1H
55.460
41.366
32.756
20.00


90
TIP3
2H
55.098
42.494
31.943
20.00


91
TIP3
OH2
44.487
25.053
41.030
20.00


92
TIP3
1H
44.965
24.874
41.840
20.00


93
TIP3
2H
43.913
25.788
41.262
20.00


94
TIP3
OH2
50.573
33.176
62.732
20.00


95
TIP3
1H
51.351
32.774
63.106
20.00


96
TIP3
2H
50.818
33.516
61.865
20.00


97
TIP3
OH2
49.953
52.982
34.749
20.00


98
TIP3
1H
49.992
52.859
35.691
20.00


99
TIP3
2H
49.758
53.917
34.634
20.00


100
TIP3
OH2
47.275
17.995
39.661
20.00


101
TIP3
1H
48.071
17.850
40.167
20.00


102
TIP3
2H
47.429
18.857
39.243
20.00


103
TIP3
OH2
71.352
29.089
36.878
20.00


104
TIP3
1H
71.322
29.074
37.839
20.00


105
TIP3
2H
71.180
29.979
36.603
20.00


106
TIP3
OH2
29.430
35.859
66.439
20.00


107
TIP3
1H
29.726
35.302
67.151
20.00


108
TIP3
2H
29.413
36.763
66.780
20.00


109
TIP3
OH2
60.271
6.760
44.654
20.00


110
TIP3
1H
60.468
6.649
45.591
20.00


111
TIP3
2H
60.190
7.711
44.594
20.00


112
TIP3
OH2
37.294
40.087
40.715
20.00


113
TIP3
1H
36.898
40.267
41.578
20.00


114
TIP3
2H
37.588
40.958
40.472
20.00


115
TIP3
OH2
43.748
16.614
44.085
20.00


116
TIP3
1H
44.120
16.513
44.960
20.00


117
TIP3
O2H
43.925
17.542
44.004
20.00


118
TIP3
OH2
68.520
39.888
46.997
20.00


119
TIP3
1H
67.991
39.691
47.769
20.00


120
TIP3
2H
67.978
40.491
46.494
20.00


121
TIP3
OH2
58.983
37.779
38.817
20.00


122
TIP3
1H
59.166
37.703
39.753
20.00


123
TIP3
2H
58.959
38.722
38.652
20.00


1
NO_H
O1
56.508
33.999
33.158
0.00


2
NO_H
C2
56.195
34.428
34.475
0.00


3
NO_H
C3
55.272
33.387
34.975
0.00


4
NO_H
C4
55.005
32.237
34.328
0.00


5
NO_H
C5
55.802
31.748
33.139
0.00


6
NO_H
C6
57.040
32.661
33.064
0.00


7
NO_H
S11
54.303
33.664
36.352
0.00


8
NO_H
C12
53.738
31.989
36.222
0.00


9
NO_H
C13
54.015
31.430
35.040
0.00


10
NO_H
C14
53.373
30.194
34.527
0.00


11
NO_H
O15
53.544
29.898
33.386
0.00


12
NO_H
O16
52.655
29.368
35.270
0.00


13
NO_H
N17
52.959
31.222
37.208
0.00


14
NO_H
C18
52.258
31.692
38.256
0.00


15
NO_H
O19
52.471
32.753
38.871
0.00


16
NO_H
C20
51.099
30.781
38.736
0.00


17
NO_H
O21
50.031
31.233
39.053
0.00


18
NO_H
O22
51.286
29.429
38.924
0.00


19
NO_H
C23
55.687
35.865
34.517
0.00


20
NO_H
N25
56.853
36.772
34.366
0.00


21
NO_H
C31
57.312
37.239
33.194
0.00


22
NO_H
C32
58.507
38.073
33.403
0.00


23
NO_H
C33
58.662
38.076
34.763
0.00


24
NO_H
C34
57.674
37.221
35.392
0.00


25
NO_H
O35
57.690
36.879
36.554
0.00


26
NO_H
O36
56.825
36.836
32.137
0.00


27
NO_H
C37
59.400
38.796
32.575
0.00


28
NO_H
C38
60.492
39.457
33.192
0.00


29
NO_H
C39
60.621
39.444
34.609
0.00


30
NO_H
C40
59.698
38.714
35.403
0.00


31
NO_H
O44
61.631
40.169
35.326
0.00


32
NO_H
C45
61.145
40.731
36.599
0.00
















TABLE C







Table of the orthogonal three dimensional coordinates in Ångstroms


and B factors (Å2) for Protein Tyrosine Phosphatase 1B complexed


with 5-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-


(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid


(Example 4).












No
Amino acid
X
Y
Z
B
















1
GLU
N
59.958
70.181
38.145
50.84


2
GLU
CA
58.803
69.268
38.132
51.38


3
GLU
C
58.809
68.319
36.855
49.72


4
GLU
O
59.460
68.640
35.857
49.04


5
GLU
CB
57.591
70.243
38.223
53.79


6
GLU
CG
56.243
69.633
38.610
57.54


7
GLU
CD
56.368
68.679
39.828
62.60


8
GLU
OE1
56.347
69.190
40.946
64.63


9
GLU
OE2
56.479
67.454
39.647
64.40


10
GLU
HA
58.898
68.637
39.019
20.00


11
GLU
1HB
57.526
70.850
37.323
20.00


12
GLU
2HB
57.818
70.928
39.043
20.00


13
GLU
1HG
55.736
69.097
37.823
20.00


14
GLU
2HG
55.552
70.439
38.879
20.00


15
MET
N
57.987
67.209
36.871
46.10


16
MET
CA
57.535
66.645
35.550
42.61


17
MET
C
56.699
67.639
34.673
40.49


18
MET
O
56.698
67.589
33.457
38.08


19
MET
CB
56.671
65.360
35.644
41.62


20
MET
CG
55.206
65.625
36.082
40.45


21
MET
SD
54.276
64.127
36.149
35.84


22
MET
CE
55.232
63.264
37.441
39.51


23
MET
H
57.559
66.997
37.759
20.00


24
MET
HA
58.440
66.400
35.000
20.00


25
MET
1HB
57.157
64.654
36.311
20.00


26
MET
2HB
56.626
64.870
34.671
20.00


27
MET
1HG
54.645
66.290
35.422
20.00


28
MET
2HG
55.188
66.074
37.082
20.00


29
MET
1HE
55.510
63.974
38.230
20.00


30
MET
2HE
56.154
62.833
37.052
20.00


31
MET
3HE
54.636
62.486
37.923
20.00


32
GLU
N
55.933
68.506
35.346
40.04


33
GLU
CA
55.048
69.427
34.645
41.99


34
GLU
C
55.841
70.396
33.686
41.64


35
GLU
O
55.416
70.753
32.599
42.33


36
GLU
CB
54.205
70.086
35.723
43.82


37
GLU
CG
52.967
70.759
35.105
47.17


38
GLU
CD
51.943
71.122
36.194
49.31


39
GLU
OE1
52.375
71.686
37.179
48.56


40
GLU
OE2
50.736
70.869
36.056
51.19


41
GLU
H
55.891
68.348
36.331
20.00


42
GLU
HA
54.387
68.813
34.030
20.00


43
GLU
1HB
54.780
70.799
36.314
20.00


44
GLU
2HB
53.860
69.333
36.440
20.00


45
GLU
1HG
52.473
70.118
34.379
20.00


46
GLU
2HG
53.234
71.688
34.607
20.00


47
LYS
N
57.077
70.711
34.138
40.99


48
LYS
CA
58.115
71.521
33.434
41.50


49
LYS
C
58.730
70.802
32.190
39.57


50
LYS
O
58.673
71.310
31.076
39.12


51
LYS
CB
59.261
71.933
34.428
45.89


52
LYS
CG
58.918
73.024
35.497
51.71


53
LYS
CD
59.986
73.136
36.630
56.13


54
LYS
CE
59.423
73.478
38.036
59.81


55
LYS
NZ
60.210
72.951
39.186
62.35


56
LYS
H
57.200
70.440
35.092
20.00


57
LYS
HA
57.601
72.409
33.064
20.00


58
LYS
1HB
60.122
72.290
33.861
20.00


59
LYS
2HB
59.590
71.028
34.944
20.00


60
LYS
1HG
57.935
72.822
35.923
20.00


61
LYS
2HG
58.812
73.990
35.000
20.00


62
LYS
1HD
60.756
73.854
36.348
20.00


63
LYS
2HD
60.497
72.177
36.711
20.00


64
LYS
1HE
58.404
73.085
38.137
20.00


65
LYS
2HE
59.313
74.564
38.135
20.00


66
LYS
1HZ
61.199
73.268
39.140
20.00


67
LYS
2HZ
60.194
71.902
39.141
20.00


68
LYS
3HZ
59.783
73.242
40.090
20.00


69
GLU
N
59.247
69.571
32.450
38.42


70
GLU
CA
59.583
68.656
31.386
37.30


71
GLU
C
58.523
68.608
30.274
34.58


72
GLU
O
58.814
68.798
29.094
33.74


73
GLU
CB
59.912
67.281
31.966
40.63


74
GLU
CG
60.000
66.235
30.835
46.16


75
GLU
CD
60.673
64.854
31.065
49.22


76
GLU
OE1
60.508
64.217
32.105
50.86


77
GLU
OE2
61.374
64.376
30.167
51.79


78
GLU
H
59.306
69.279
33.408
20.00


79
GLU
HA
60.487
69.052
30.916
20.00


80
GLU
1HB
59.208
66.970
32.737
20.00


81
GLU
2HB
60.879
67.339
32.462
20.00


82
GLU
1HG
60.482
66.668
29.959
20.00


83
GLU
2HG
58.967
66.050
30.534
20.00


84
PHE
N
57.266
68.373
30.681
31.46


85
PHE
CA
56.238
68.253
29.653
30.49


86
PHE
C
56.102
69.457
28.733
33.05


87
PHE
O
56.072
69.315
27.517
31.17


88
PHE
CB
54.928
67.999
30.280
26.00


89
PHE
CG
53.774
67.886
29.306
23.39


90
PHE
CD1
53.283
66.628
28.992
24.75


91
PHE
CD2
53.136
69.002
28.777
23.83


92
PHE
CE1
52.145
66.498
28.272
21.69


93
PHE
CE2
52.023
68.860
27.977
23.15


94
PHE
CZ
51.514
67.599
27.755
22.50


95
PHE
H
57.145
68.129
31.644
20.00


96
PHE
HA
56.531
67.409
29.021
20.00


97
PHE
1HB
54.687
68.795
30.988
20.00


98
PHE
2HB
54.998
67.080
30.860
20.00


99
PHE
HD1
53.805
65.747
29.338
20.00


100
PHE
HD2
53.488
70.001
29.012
20.00


101
PHE
HE1
51.759
65.506
28.091
20.00


102
PHE
HE2
51.544
69.725
27.536
20.00


103
PHE
HZ
50.632
67.461
27.165
20.00


104
GLU
N
56.018
70.665
29.336
34.78


105
GLU
CA
55.897
71.897
28.527
36.92


106
GLU
C
57.122
72.019
27.553
34.88


107
GLU
O
57.053
72.444
26.408
34.89


108
GLU
CB
55.852
73.091
29.484
42.69


109
GLU
CG
54.488
73.612
30.017
51.81


110
GLU
CD
54.564
75.215
30.166
58.22


111
GLU
OE1
55.679
75.818
30.045
60.76


112
GLU
OE2
53.497
75.845
30.355
60.88


113
GLU
H
55.958
70.729
30.335
20.00


114
GLU
HA
54.994
71.824
27.915
20.00


115
GLU
1HB
56.246
73.911
28.885
20.00


116
GLU
2HB
56.555
72.973
30.310
20.00


117
GLU
1HG
54.203
73.129
30.954
20.00


118
GLU
2HG
53.684
73.380
29.316
20.00


119
GLN
N
58.282
71.586
28.060
32.17


120
GLN
CA
59.556
71.631
27.323
32.79


121
GLN
C
59.615
70.636
26.126
32.59


122
GLN
O
60.173
71.008
25.095
33.38


123
GLN
CB
60.597
71.291
28.375
38.01


124
GLN
CG
62.059
71.020
27.998
46.72


125
GLN
CD
62.634
70.285
29.249
54.60


126
GLN
OE1
62.587
69.070
29.367
58.48


127
GLN
NE2
63.129
71.080
30.204
57.65


128
GLN
H
58.242
71.334
29.034
20.00


129
GLN
HA
59.693
72.651
26.984
20.00


130
GLN
1HB
60.256
70.391
28.865
20.00


131
GLN
2HB
60.549
72.041
29.167
20.00


132
GLN
1HG
62.601
71.953
27.837
20.00


133
GLN
2HG
62.187
70.379
27.126
20.00


134
GLN
1HE2
63.670
70.582
30.873
20.00


135
GLN
2HE2
62.955
72.054
30.303
20.00


136
ILE
N
59.048
69.416
26.317
30.75


137
ILE
CA
58.941
68.342
25.297
29.79


138
ILE
C
57.992
68.730
24.090
29.61


139
ILE
O
58.254
68.655
22.886
28.92


140
ILE
CB
58.520
66.966
25.824
28.01


141
ILE
CG1
59.648
66.484
26.709
26.65


142
ILE
CG2
58.389
65.988
24.623
24.67


143
ILE
CD1
59.272
65.414
27.633
30.61


144
ILE
H
58.661
69.264
27.231
20.00


145
ILE
HA
59.984
68.125
25.132
20.00


146
ILE
HB
57.585
67.027
26.380
20.00


147
ILE
1HG1
60.041
67.301
27.314
20.00


148
ILE
2HG1
60.483
66.163
26.083
20.00


149
ILE
1HG2
59.307
65.970
24.039
20.00


150
ILE
2HG2
57.582
66.246
23.946
20.00


151
ILE
3HG2
58.243
64.972
24.970
20.00


152
ILE
1HD1
58.868
64.551
27.108
20.00


153
ILE
2HD1
58.551
65.761
28.375
20.00


154
ILE
3HD1
60.223
65.162
28.094
20.00


155
ASP
N
56.856
69.222
24.608
30.56


156
ASP
CA
55.774
69.774
23.845
34.30


157
ASP
C
56.317
70.948
23.013
36.61


158
ASP
O
56.305
70.858
21.794
37.72


159
ASP
CB
54.623
70.039
24.829
34.23


160
ASP
CG
53.266
69.515
24.380
34.09


161
ASP
OD1
53.161
68.398
23.871
34.45


162
ASP
OD2
52.282
70.192
24.584
35.24


163
ASP
H
56.711
69.214
25.597
20.00


164
ASP
HA
55.509
68.998
23.135
20.00


165
ASP
1HB
54.530
71.096
25.058
20.00


166
ASP
2HB
54.782
69.545
25.769
20.00


167
LYS
N
56.891
71.996
23.669
38.57


168
LYS
CA
57.394
73.143
22.870
40.78


169
LYS
C
58.187
72.746
21.598
40.89


170
LYS
O
57.821
73.058
20.475
41.19


171
LYS
CB
58.195
74.152
23.704
44.73


172
LYS
CG
59.737
74.010
23.716
49.46


173
LYS
CD
60.389
74.662
24.948
52.61


174
LYS
CE
61.863
74.244
25.156
51.86


175
LYS
NZ
62.098
72.811
24.890
49.92


176
LYS
H
56.748
71.985
24.653
20.00


177
LYS
HA
56.492
73.642
22.511
20.00


178
LYS
1HB
57.810
74.129
24.724
20.00


179
LYS
2HB
57.962
75.153
23.339
20.00


180
LYS
1HG
60.175
74.398
22.793
20.00


181
LYS
2HG
59.978
72.965
23.809
20.00


182
LYS
1HD
59.811
74.375
25.827
20.00


183
LYS
2HD
60.301
75.749
24.895
20.00


184
LYS
1HE
62.176
74.480
26.182
20.00


185
LYS
2HE
62.505
74.843
24.502
20.00


186
LYS
1HZ
61.912
72.594
23.887
20.00


187
LYS
2HZ
61.421
72.194
25.397
20.00


188
LYS
3HZ
63.067
72.497
25.108
20.00


189
SER
N
59.282
72.003
21.844
39.93


190
SER
CA
60.160
71.674
20.742
41.11


191
SER
C
59.713
70.466
19.823
41.60


192
SER
O
60.502
69.985
19.006
44.13


193
SER
CB
61.342
71.196
21.527
41.13


194
SER
OG
60.972
70.326
22.646
43.06


195
SER
H
59.394
71.615
22.757
20.00


196
SER
HA
60.414
72.549
20.149
20.00


197
SER
1HB
61.840
72.111
21.923
20.00


198
SER
2HB
62.201
70.871
20.872
20.00


199
SER
HG
60.144
69.739
22.668
20.00


200
GLY
N
58.471
69.970
20.020
39.95


201
GLY
CA
58.004
68.791
19.312
36.83


202
GLY
C
58.868
67.488
19.463
35.39


203
GLY
O
59.151
66.807
18.529
37.15


204
GLY
H
57.818
70.556
20.489
20.00


205
GLY
1HA
57.969
69.018
18.241
20.00


206
GLY
2HA
57.004
68.542
19.656
20.00


207
SER
N
59.300
67.067
20.659
32.66


208
SER
CA
60.096
65.891
20.842
31.67


209
SER
C
59.562
64.556
21.564
29.26


210
SER
O
60.362
63.696
21.864
28.04


211
SER
CB
61.523
66.205
21.262
32.05


212
SER
OG
61.785
67.365
22.072
36.33


213
SER
H
58.976
67.617
21.428
20.00


214
SER
HA
60.276
65.532
19.858
20.00


215
SER
1HB
62.162
66.169
20.334
20.00


216
SER
2HB
61.990
65.313
21.767
20.00


217
SER
HG
61.143
68.124
22.244
20.00


218
TRP
N
58.263
64.341
21.705
26.65


219
TRP
CA
57.678
63.094
22.236
21.95


220
TRP
C
58.092
61.836
21.456
21.43


221
TRP
O
58.398
60.796
21.999
21.86


222
TRP
CB
56.162
63.309
22.226
22.70


223
TRP
CG
55.712
64.329
23.250
20.91


224
TRP
CD1
55.145
65.601
23.071
21.20


225
TRP
CD2
55.791
64.152
24.658
21.02


226
TRP
NE1
54.895
66.197
24.287
21.97


227
TRP
CE2
55.270
65.323
25.295
20.57


228
TRP
CE3
56.277
63.109
25.402
18.68


229
TRP
CZ2
55.184
65.387
26.676
20.86


230
TRP
CZ3
56.215
63.188
26.788
16.67


231
TRP
CH2
55.658
64.311
27.429
19.85


232
TRP
H
57.686
65.143
21.597
20.00


233
TRP
HA
58.058
62.950
23.247
20.00


234
TRP
1HB
55.644
62.373
22.446
20.00


235
TRP
2HB
55.835
63.613
21.232
20.00


236
TRP
HD1
54.914
66.062
22.121
20.00


237
TRP
HE1
54.495
67.092
24.417
20.00


238
TRP
HE3
56.679
62.229
24.906
20.00


239
TRP
HZ2
54.819
66.296
27.119
20.00


240
TRP
HZ3
56.622
62.372
27.369
20.00


241
TRP
HH2
55.652
64.334
28.506
20.00


242
ALA
N
58.142
61.898
20.137
21.75


243
ALA
CA
58.747
60.754
19.397
21.29


244
ALA
C
60.219
60.530
19.762
19.48


245
ALA
O
60.614
59.444
20.080
17.73


246
ALA
CB
58.536
60.943
17.876
21.57


247
ALA
H
57.792
62.693
19.657
20.00


248
ALA
HA
58.226
59.852
19.697
20.00


249
ALA
1HB
59.132
61.760
17.471
20.00


250
ALA
2HB
57.493
61.183
17.683
20.00


251
ALA
3HB
58.789
60.035
17.340
20.00


252
ALA
N
61.000
61.573
19.777
21.34


253
ALA
CA
62.397
61.371
20.129
20.36


254
ALA
C
62.640
60.772
21.579
20.18


255
ALA
O
63.307
59.773
21.765
23.47


256
ALA
CB
62.920
62.788
20.000
21.69


257
ALA
H
60.646
62.340
19.255
20.00


258
ALA
HA
62.858
60.692
19.413
20.00


259
ALA
1HB
62.433
63.449
20.701
20.00


260
ALA
2HB
62.763
63.151
18.988
20.00


261
ALA
3HB
63.990
62.798
20.177
20.00


262
ILE
N
61.932
61.425
22.576
20.36


263
ILE
CA
61.790
60.947
23.989
20.21


264
ILE
C
61.398
59.404
24.061
19.21


265
ILE
O
62.077
58.599
24.654
20.20


266
ILE
CB
60.737
61.851
24.792
21.58


267
ILE
CG1
60.968
63.384
24.927
25.33


268
ILE
CG2
60.518
61.317
26.196
23.50


269
ILE
CD1
62.410
63.607
25.264
26.28


270
ILE
H
61.488
62.254
22.255
20.00


271
ILE
HA
62.789
61.058
24.405
20.00


272
ILE
HB
59.791
61.736
24.267
20.00


273
ILE
1HG1
60.325
63.814
25.692
20.00


274
ILE
2HG1
60.743
63.949
24.032
20.00


275
ILE
1HG2
61.434
61.342
26.788
20.00


276
ILE
2HG2
60.157
60.290
26.217
20.00


277
ILE
3HG2
59.791
61.912
26.743
20.00


278
ILE
1HD1
63.073
63.217
24.492
20.00


279
ILE
2HD1
62.691
63.122
26.198
20.00


280
ILE
3HD1
62.627
64.673
25.357
20.00


281
TYR
N
60.231
59.064
23.403
18.90


282
TYR
CA
59.663
57.728
23.212
16.59


283
TYR
C
60.620
56.761
22.628
19.69


284
TYR
O
60.722
55.641
23.044
21.05


285
TYR
CB
58.346
57.810
22.413
15.48


286
TYR
CG
57.722
56.420
22.275
15.58


287
TYR
CD1
57.298
55.713
23.438
15.71


288
TYR
CD2
57.586
55.775
21.044
17.07


289
TYR
CE1
56.771
54.396
23.415
15.33


290
TYR
CE2
57.097
54.458
20.983
18.24


291
TYR
CZ
56.694
53.755
22.144
17.83


292
TYR
OH
56.243
52.455
21.973
16.43


293
TYR
H
59.824
59.847
22.928
20.00


294
TYR
HA
59.466
57.370
24.214
20.00


295
TYR
1HB
58.526
58.248
21.425
20.00


296
TYR
2HB
57.651
58.450
22.951
20.00


297
TYR
HD1
57.367
56.218
24.392
20.00


298
TYR
HD2
57.892
56.285
20.136
20.00


299
TYR
HE1
56.386
54.090
24.384
20.00


300
TYR
HE2
56.999
53.996
20.016
20.00


301
TYR
HH
56.824
51.863
22.447
20.00


302
GLN
N
61.366
57.183
21.632
20.71


303
GLN
CA
62.379
56.353
21.092
23.54


304
GLN
C
63.491
56.092
22.091
21.33


305
GLN
O
63.866
54.931
22.226
22.52


306
GLN
CB
62.737
56.837
19.717
29.74


307
GLN
CG
61.480
56.551
18.818
43.77


308
GLN
CD
61.124
57.664
17.789
50.76


309
GLN
OE1
61.317
58.863
17.906
53.37


310
GLN
NE2
60.647
57.254
16.639
51.41


311
GLN
H
61.282
58.134
21.330
20.00


312
GLN
HA
61.918
55.375
20.947
20.00


313
GLN
1HB
63.576
56.262
19.335
20.00


314
GLN
2HB
63.034
57.885
19.731
20.00


315
GLN
1HG
60.567
56.384
19.385
20.00


316
GLN
2HG
61.648
55.643
18.247
20.00


317
GLN
1HE2
60.739
58.175
16.252
20.00


318
GLN
2HE2
60.319
56.444
16.170
20.00


319
ASP
N
63.890
57.146
22.820
22.69


320
ASP
CA
64.915
56.979
23.869
23.75


321
ASP
C
64.453
55.995
24.956
21.78


322
ASP
O
65.227
55.192
25.428
21.26


323
ASP
CB
65.301
58.315
24.526
26.73


324
ASP
CG
65.718
59.428
23.564
31.02


325
ASP
OD1
66.369
59.105
22.550
31.00


326
ASP
OD2
65.408
60.604
23.837
32.48


327
ASP
H
63.674
58.089
22.539
20.00


328
ASP
HA
65.794
56.545
23.392
20.00


329
ASP
1HB
66.116
58.169
25.233
20.00


330
ASP
2HB
64.466
58.694
25.112
20.00


331
ILE
N
63.136
56.005
25.269
20.63


332
ILE
CA
62.626
54.892
26.106
19.38


333
ILE
C
62.664
53.512
25.346
19.66


334
ILE
O
63.081
52.492
25.913
18.07


335
ILE
CB
61.192
55.230
26.721
19.75


336
ILE
CG1
61.197
56.210
27.894
19.61


337
ILE
CG2
60.570
54.008
27.384
16.65


338
ILE
CD1
59.917
57.001
28.052
21.44


339
ILE
H
62.684
56.835
24.927
20.00


340
ILE
HA
63.327
54.768
26.932
20.00


341
ILE
HB
60.568
55.595
25.907
20.00


342
ILE
1HG1
61.987
56.937
27.696
20.00


343
ILE
2HG1
61.490
55.748
28.838
20.00


344
ILE
1HG2
61.179
53.628
28.194
20.00


345
ILE
2HG2
60.422
53.213
26.655
20.00


346
ILE
3HG2
59.582
54.249
27.768
20.00


347
ILE
1HD1
59.114
56.434
28.480
20.00


348
ILE
2HD1
59.594
57.364
27.080
20.00


349
ILE
3HD1
60.051
57.880
28.668
20.00


350
ARG
N
62.162
53.475
24.066
19.64


351
ARG
CA
62.288
52.251
23.267
22.20


352
ARG
C
63.742
51.742
23.370
22.74


353
ARG
O
63.964
50.589
23.705
20.20


354
ARG
CB
61.788
52.370
21.795
23.80


355
ARG
CG
60.263
52.326
21.416
29.28


356
ARG
CD
59.846
51.717
19.966
38.17


357
ARG
NE
58.356
51.345
19.989
47.71


358
ARG
CZ
57.194
51.166
19.228
46.22


359
ARG
NH1
57.118
51.134
17.914
51.10


360
ARG
NH2
56.016
50.979
19.791
39.82


361
ARG
H
61.917
54.354
23.659
20.00


362
ARG
HA
61.656
51.528
23.768
20.00


363
ARG
1HB
62.257
51.547
21.248
20.00


364
ARG
2HB
62.258
53.237
21.335
20.00


365
ARG
1HG
59.801
53.297
21.613
20.00


366
ARG
2HG
59.896
51.626
22.154
20.00


367
ARG
1HD
60.387
50.786
19.796
20.00


368
ARG
2HD
60.080
52.412
19.161
20.00


369
ARG
HE
58.008
51.167
20.902
20.00


370
ARG
1HH1
56.227
51.223
17.478
20.00


371
ARG
2HH1
57.905
50.928
17.355
20.00


372
ARG
1HH2
55.262
50.537
19.303
20.00


373
ARG
2HH2
55.845
51.282
20.734
20.00


374
HIS
N
64.746
52.610
23.202
20.00


375
HIS
CA
66.074
51.898
23.241
20.00


376
HIS
C
66.658
51.767
24.678
20.00


377
HIS
O
67.428
50.861
24.973
20.00


378
HIS
CB
67.188
52.616
22.410
20.00


379
HIS
CG
66.701
53.751
21.532
20.00


380
HIS
ND1
66.063
53.572
20.339
20.00


381
HIS
CD2
66.954
55.115
21.693
20.00


382
HIS
CE1
65.963
54.797
19.797
20.00


383
HIS
NE2
66.488
55.736
20.591
20.00


384
HIS
H
64.728
53.577
22.922
20.00


385
HIS
HA
65.925
50.904
22.851
20.00


386
HIS
1HB
67.950
53.016
23.105
20.00


387
HIS
2HB
67.710
51.887
21.787
20.00


388
HIS
HD1
65.792
52.727
19.934
20.00


389
HIS
HD2
67.557
55.565
22.468
20.00


390
HIS
HE1
65.731
54.961
18.764
20.00


391
GLU
N
66.332
52.581
25.699
24.60


392
GLU
CA
66.817
52.241
27.039
23.35


393
GLU
C
66.236
50.854
27.523
20.84


394
GLU
O
66.743
50.234
28.462
20.77


395
GLU
CB
66.563
53.445
27.980
25.78


396
GLU
CG
67.579
54.531
27.671
34.71


397
GLU
CD
67.550
55.857
28.464
41.97


398
GLU
OE1
67.473
55.873
29.688
47.08


399
GLU
OE2
67.723
56.887
27.831
42.03


400
GLU
H
65.826
53.435
25.569
20.00


401
GLU
HA
67.896
52.124
26.937
20.00


402
GLU
1HB
66.656
53.140
29.019
20.00


403
GLU
2HB
65.552
53.848
27.866
20.00


404
GLU
1HG
67.556
54.790
26.615
20.00


405
GLU
2HG
68.561
54.116
27.863
20.00


406
ALA
N
65.138
50.381
26.878
20.22


407
ALA
CA
64.425
49.305
27.596
18.85


408
ALA
C
65.171
47.952
27.675
19.60


409
ALA
O
66.080
47.612
26.913
21.31


410
ALA
CB
62.979
49.307
27.198
17.65


411
ALA
H
64.736
50.905
26.129
20.00


412
ALA
HA
64.411
49.635
28.630
20.00


413
ALA
1HB
62.886
49.086
26.128
20.00


414
ALA
2HB
62.566
50.300
27.380
20.00


415
ALA
3HB
62.406
48.566
27.755
20.00


416
SER
N
64.735
47.217
28.738
17.44


417
SER
CA
65.303
45.958
29.138
17.65


418
SER
C
65.080
44.926
28.069
20.44


419
SER
O
64.118
44.975
27.295
20.82


420
SER
CB
64.662
45.552
30.486
16.87


421
SER
OG
64.525
46.634
31.510
17.03


422
SER
H
63.945
47.581
29.221
20.00


423
SER
HA
66.386
46.074
29.221
20.00


424
SER
1HB
65.308
44.740
30.885
20.00


425
SER
2HB
63.712
44.975
30.299
20.00


426
SER
HG
64.529
47.621
31.322
20.00


427
ASP
N
65.958
43.934
28.082
23.65


428
ASP
CA
65.585
42.963
27.136
25.32


429
ASP
C
66.051
41.684
27.689
24.00


430
ASP
O
67.238
41.557
27.964
25.47


431
ASP
CB
66.321
43.342
25.827
30.03


432
ASP
CG
66.013
42.208
24.837
35.94


433
ASP
OD1
64.835
41.789
24.742
37.82


434
ASP
OD2
66.971
41.731
24.221
40.50


435
ASP
H
66.864
43.946
28.494
20.00


436
ASP
HA
64.508
42.853
26.973
20.00


437
ASP
1HB
67.406
43.380
25.994
20.00


438
ASP
2HB
66.013
44.285
25.384
20.00


439
PHE
N
65.113
40.763
27.872
20.26


440
PHE
CA
65.402
39.506
28.474
17.74


441
PHE
C
64.786
38.500
27.583
19.63


442
PHE
O
63.886
38.850
26.811
18.88


443
PHE
CB
64.780
39.359
29.899
15.74


444
PHE
CG
65.255
40.400
30.868
14.99


445
PHE
CD1
66.433
40.210
31.547
14.29


446
PHE
CD2
64.503
41.531
31.095
11.07


447
PHE
CE1
66.871
41.163
32.441
13.28


448
PHE
CE2
64.910
42.478
32.012
12.04


449
PHE
CZ
66.114
42.290
32.698
14.86


450
PHE
H
64.258
40.990
27.405
20.00


451
PHE
HA
66.483
39.375
28.481
20.00


452
PHE
1HB
64.945
38.372
30.333
20.00


453
PHE
2HB
63.697
39.445
29.816
20.00


454
PHE
HD1
67.024
39.314
31.395
20.00


455
PHE
HD2
63.562
41.653
30.585
20.00


456
PHE
HE1
67.800
41.004
32.982
20.00


457
PHE
HE2
64.290
43.328
32.250
20.00


458
PHE
HZ
66.455
43.015
33.431
20.00


459
PRO
N
65.253
37.196
27.759
19.03


460
PRO
CA
64.636
36.040
27.082
17.74


461
PRO
C
63.151
35.749
27.411
17.59


462
PRO
O
62.694
35.796
28.535
18.11


463
PRO
CB
65.582
34.833
27.412
17.29


464
PRO
CG
66.564
35.298
28.571
17.67


465
PRO
CD
66.467
36.813
28.562
17.97


466
PRO
HA
64.674
36.227
26.012
20.00


467
PRO
1HB
66.190
34.622
26.529
20.00


468
PRO
2HB
65.034
33.928
27.683
20.00


469
PRO
1HG
66.200
34.943
29.539
20.00


470
PRO
2HG
67.592
34.936
28.459
20.00


471
PRO
1HD
67.323
37.192
28.014
20.00


472
PRO
2HD
66.501
37.258
29.556
20.00


473
CYS
N
62.429
35.432
26.359
16.91


474
CYS
CA
61.116
34.821
26.476
16.83


475
CYS
C
61.155
33.441
25.799
17.10


476
CYS
O
60.446
33.139
24.838
15.98


477
CYS
CB
60.141
35.734
25.788
17.42


478
CYS
SG
60.311
37.521
26.025
21.76


479
CYS
H
62.845
35.661
25.483
20.00


480
CYS
HA
60.833
34.706
27.525
20.00


481
CYS
1HB
59.112
35.435
26.009
20.00


482
CYS
2HB
60.247
35.600
24.709
20.00


483
CYS
HG
61.234
38.020
25.205
20.00


484
ARG
N
62.055
32.618
26.311
17.15


485
ARG
CA
62.240
31.246
25.729
19.32


486
ARG
C
61.030
30.297
25.783
19.49


487
ARG
O
60.747
29.643
24.808
19.32


488
ARG
CB
63.463
30.474
26.274
24.18


489
ARG
CG
64.803
30.648
25.474
34.75


490
ARG
CD
66.027
31.366
26.089
42.80


491
ARG
NE
65.822
31.308
27.538
51.13


492
ARG
CZ
66.692
31.456
28.527
51.47


493
ARG
NH1
67.986
31.573
28.252
48.86


494
ARG
NH2
66.143
31.494
29.730
48.27


495
ARG
H
62.418
32.881
27.211
20.00


496
ARG
HA
62.407
31.422
24.671
20.00


497
ARG
1HB
63.253
29.408
26.156
20.00


498
ARG
2HB
63.503
30.537
27.360
20.00


499
ARG
1HG
64.620
31.011
24.461
20.00


500
ARG
2HG
65.175
29.633
25.308
20.00


501
ARG
1HD
66.058
32.421
25.820
20.00


502
ARG
2HD
66.979
30.904
25.819
20.00


503
ARG
HE
64.881
31.300
27.880
20.00


504
ARG
1HH1
68.672
31.709
28.970
20.00


505
ARG
2HH1
68.274
31.511
27.301
20.00


506
ARG
1HH2
66.703
31.481
30.549
20.00


507
ARG
2HH2
65.138
31.551
29.794
20.00


508
VAL
N
60.319
30.155
26.945
17.97


509
VAL
CA
59.174
29.238
26.975
16.80


510
VAL
C
58.113
29.793
26.009
15.05


511
VAL
O
57.497
29.009
25.329
15.45


512
VAL
CB
58.828
28.750
28.462
18.01


513
VAL
CG1
57.372
28.681
28.911
15.99


514
VAL
CG2
59.711
29.222
29.601
17.07


515
VAL
H
60.614
30.724
27.716
20.00


516
VAL
HA
59.553
28.350
26.498
20.00


517
VAL
HB
59.085
27.690
28.412
20.00


518
VAL
1HG1
56.744
28.248
28.134
20.00


519
VAL
2HG1
56.988
29.671
29.154
20.00


520
VAL
3HG1
57.249
28.037
29.790
20.00


521
VAL
1HG2
59.485
30.243
29.907
20.00


522
VAL
2HG2
60.768
29.174
29.338
20.00


523
VAL
3HG2
59.588
28.576
30.471
20.00


524
ALA
N
57.929
31.159
25.879
14.53


525
ALA
CA
56.893
31.736
24.965
14.43


526
ALA
C
57.034
31.215
23.579
15.46


527
ALA
O
56.026
30.897
22.995
16.10


528
ALA
CB
56.950
33.283
24.793
12.61


529
ALA
H
58.489
31.728
26.477
20.00


530
ALA
HA
55.936
31.377
25.317
20.00


531
ALA
1HB
57.978
33.586
24.605
20.00


532
ALA
2HB
56.694
33.786
25.717
20.00


533
ALA
3HB
56.439
33.685
23.923
20.00


534
LYS
N
58.297
31.191
23.122
17.52


535
LYS
CA
58.835
30.716
21.906
17.70


536
LYS
C
58.993
29.228
21.723
19.60


537
LYS
O
59.486
28.823
20.702
22.60


538
LYS
CB
60.168
31.413
21.780
19.24


539
LYS
CG
60.083
32.927
21.737
19.97


540
LYS
CD
59.064
33.361
20.674
21.69


541
LYS
CE
59.193
34.787
20.078
24.74


542
LYS
NZ
58.108
35.143
19.082
26.46


543
LYS
H
58.962
31.547
23.782
20.00


544
LYS
HA
58.145
31.021
21.117
20.00


545
LYS
1HB
60.687
31.055
20.890
20.00


546
LYS
2HB
60.838
31.130
22.595
20.00


547
LYS
1HG
61.064
33.367
21.526
20.00


548
LYS
2HG
59.740
33.340
22.686
20.00


549
LYS
1HD
58.049
33.228
21.050
20.00


550
LYS
2HD
59.142
32.677
19.824
20.00


551
LYS
1HE
60.168
34.871
19.582
20.00


552
LYS
2HE
59.209
35.527
20.883
20.00


553
LYS
1HZ
57.167
35.181
19.539
20.00


554
LYS
2HZ
58.096
34.490
18.275
20.00


555
LYS
3HZ
58.222
36.119
18.723
20.00


556
LEU
N
58.600
28.321
22.639
20.39


557
LEU
CA
58.649
26.874
22.415
19.13


558
LEU
C
57.499
26.495
21.561
21.96


559
LEU
O
56.401
27.065
21.641
20.82


560
LEU
CB
58.382
26.108
23.763
18.89


561
LEU
CG
59.526
26.182
24.733
17.87


562
LEU
CD1
60.698
25.466
24.168
19.14


563
LEU
CD2
59.172
25.541
26.090
17.39


564
LEU
H
58.246
28.683
23.495
20.00


565
LEU
HA
59.615
26.655
21.958
20.00


566
LEU
1HB
58.175
25.056
23.593
20.00


567
LEU
2HB
57.485
26.522
24.240
20.00


568
LEU
HG
59.806
27.235
24.855
20.00


569
LEU
1HD1
61.105
25.936
23.272
20.00


570
LEU
2HD1
60.454
24.433
23.933
20.00


571
LEU
3HD1
61.510
25.440
24.897
20.00


572
LEU
1HD2
58.924
24.482
25.978
20.00


573
LEU
2HD2
58.292
26.034
26.506
20.00


574
LEU
3HD2
59.988
25.638
26.811
20.00


575
PRO
N
57.678
25.487
20.700
23.61


576
PRO
CA
56.624
25.246
19.703
24.44


577
PRO
C
55.294
24.893
20.278
22.23


578
PRO
O
54.301
25.224
19.668
23.82


579
PRO
CB
57.127
24.113
18.808
26.16


580
PRO
CG
58.632
24.213
19.010
27.75


581
PRO
CD
58.950
24.825
20.348
26.72


582
PRO
HA
56.514
26.154
19.103
20.00


583
PRO
1HB
56.822
24.188
17.756
20.00


584
PRO
2HB
56.800
23.128
19.167
20.00


585
PRO
1HG
59.145
23.261
18.859
20.00


586
PRO
2HG
59.017
24.887
18.240
20.00


587
PRO
1HD
59.763
25.549
20.239
20.00


588
PRO
2HD
59.256
24.094
21.089
20.00


589
LYS
N
55.275
24.280
21.486
22.30


590
LYS
CA
53.990
23.915
22.172
22.26


591
LYS
C
53.174
25.094
22.666
22.91


592
LYS
O
51.958
24.974
22.806
25.95


593
LYS
CB
54.084
22.876
23.305
23.13


594
LYS
CG
54.925
23.304
24.549
24.19


595
LYS
CD
54.938
22.261
25.694
27.45


596
LYS
CE
55.785
22.825
26.873
31.65


597
LYS
NZ
55.815
22.067
28.141
37.10


598
LYS
H
56.127
23.877
21.799
20.00


599
LYS
HA
53.394
23.472
21.378
20.00


600
LYS
1HB
54.522
21.963
22.895
20.00


601
LYS
2HB
53.080
22.604
23.629
20.00


602
LYS
1HG
54.556
24.257
24.934
20.00


603
LYS
2HG
55.948
23.498
24.234
20.00


604
LYS
1HD
55.299
21.288
25.356
20.00


605
LYS
2HD
53.903
22.109
26.017
20.00


606
LYS
1HE
55.373
23.814
27.106
20.00


607
LYS
2HE
56.810
23.019
26.530
20.00


608
LYS
1HZ
56.128
21.082
28.050
20.00


609
LYS
2HZ
54.827
22.030
28.497
20.00


610
LYS
3HZ
56.381
22.529
28.880
20.00


611
ASN
N
53.890
26.227
22.879
20.49


612
ASN
CA
53.214
27.434
23.253
18.95


613
ASN
C
52.746
28.350
22.087
19.83


614
ASN
O
52.113
29.392
22.300
16.61


615
ASN
CB
54.191
28.118
24.160
15.32


616
ASN
CG
54.146
27.319
25.455
18.08


617
ASN
OD1
53.155
26.658
25.743
16.89


618
ASN
ND2
55.231
27.426
26.237
17.04


619
ASN
H
54.866
26.232
22.663
20.00


620
ASN
HA
52.284
27.169
23.748
20.00


621
ASN
1HB
53.876
29.132
24.406
20.00


622
ASN
2HB
55.207
28.155
23.763
20.00


623
ASN
1HD2
55.118
26.972
27.105
20.00


624
ASN
2HD2
56.036
27.928
25.914
20.00


625
LYS
N
53.052
27.988
20.818
19.50


626
LYS
CA
52.880
28.993
19.736
20.65


627
LYS
C
51.462
29.515
19.709
17.99


628
LYS
O
51.176
30.690
19.685
17.79


629
LYS
CB
53.224
28.321
18.344
24.77


630
LYS
CG
53.732
29.255
17.235
35.23


631
LYS
CD
54.019
28.612
15.850
43.17


632
LYS
CE
54.433
29.635
14.731
48.79


633
LYS
NZ
54.133
29.061
13.411
51.89


634
LYS
H
53.580
27.148
20.703
20.00


635
LYS
HA
53.557
29.817
19.962
20.00


636
LYS
1HB
52.351
27.791
17.957
20.00


637
LYS
2HB
53.960
27.534
18.498
20.00


638
LYS
1HG
54.655
29.727
17.587
20.00


639
LYS
2HG
53.003
30.061
17.104
20.00


640
LYS
1HD
53.098
28.115
15.541
20.00


641
LYS
2HD
54.759
27.817
15.949
20.00


642
LYS
1HE
55.496
29.890
14.790
20.00


643
LYS
2HE
53.870
30.569
14.815
20.00


644
LYS
1HZ
53.097
29.011
13.287
20.00


645
LYS
2HZ
54.453
28.080
13.339
20.00


646
LYS
3HZ
54.503
29.603
12.605
20.00


647
ASN
N
50.566
28.527
19.762
16.87


648
ASN
CA
49.107
28.843
19.726
17.37


649
ASN
C
48.464
29.507
21.029
14.52


650
ASN
O
47.248
29.727
21.164
14.87


651
ASN
CB
48.373
27.533
19.306
17.56


652
ASN
CG
48.272
26.488
20.402
21.16


653
ASN
OD1
48.877
26.514
21.451
23.28


654
ASN
ND2
47.525
25.472
20.024
22.37


655
ASN
H
50.925
27.620
19.959
20.00


656
ASN
HA
48.961
29.568
18.921
20.00


657
ASN
1HB
48.842
27.093
18.437
20.00


658
ASN
2HB
47.350
27.783
19.013
20.00


659
ASN
1HD2
47.520
24.710
20.667
20.00


660
ASN
2HD2
47.013
25.510
19.175
20.00


661
ARG
N
49.398
29.743
21.971
13.45


662
ARG
CA
49.080
30.421
23.219
14.08


663
ARG
C
49.442
31.897
23.164
11.72


664
ARG
O
49.239
32.606
24.120
11.90


665
ARG
CB
49.812
29.746
24.405
14.72


666
ARG
CG
49.139
28.440
24.752
15.03


667
ARG
CD
49.763
27.746
25.988
13.22


668
ARG
NE
48.959
26.521
26.267
14.96


669
ARG
CZ
48.858
25.909
27.402
15.87


670
ARG
NH1
49.281
26.474
28.507
14.76


671
ARG
NH2
48.299
24.741
27.436
16.81


672
ARG
H
50.337
29.472
21.776
20.00


673
ARG
HA
48.004
30.372
23.369
20.00


674
ARG
1HB
49.727
30.401
25.279
20.00


675
ARG
2HB
50.877
29.631
24.213
20.00


676
ARG
1HG
49.197
27.772
23.893
20.00


677
ARG
2HG
48.078
28.628
24.920
20.00


678
ARG
1HD
49.685
28.396
26.850
20.00


679
ARG
2HD
50.798
27.458
25.812
20.00


680
ARG
HE
48.517
26.130
25.480
20.00


681
ARG
1HH1
49.168
26.032
29.395
20.00


682
ARG
2HH1
49.705
27.377
28.439
20.00


683
ARG
1HH2
48.173
24.251
28.303
20.00


684
ARG
2HH2
47.960
24.316
26.599
20.00


685
ASN
N
49.996
32.318
22.035
12.70


686
ASN
CA
50.406
33.706
21.870
12.44


687
ASN
C
49.508
34.267
20.783
12.58


688
ASN
O
49.360
33.682
19.731
11.79


689
ASN
CB
51.893
33.770
21.499
15.34


690
ASN
CG
52.706
33.250
22.622
15.14


691
ASN
OD1
52.540
33.681
23.718
13.40


692
ASN
ND2
53.664
32.406
22.420
15.01


693
ASN
H
50.101
31.681
21.265
20.00


694
ASN
HA
50.227
34.257
22.794
20.00


695
ASN
1HB
52.211
34.789
21.274
20.00


696
ASN
2HB
52.099
33.162
20.620
20.00


697
ASN
1HD2
54.227
32.167
23.194
20.00


698
ASN
2HD2
53.844
32.004
21.533
20.00


699
ARG
N
48.922
35.407
21.070
11.31


700
ARG
CA
48.157
36.050
20.031
10.21


701
ARG
C
49.030
36.735
18.938
11.77


702
ARG
O
48.660
36.681
17.785
10.43


703
ARG
CB
47.337
37.044
20.779
10.53


704
ARG
CG
46.560
37.866
19.869
9.14


705
ARG
CD
45.810
38.876
20.590
10.01


706
ARG
NE
44.644
38.387
21.426
10.47


707
ARG
CZ
43.536
38.042
20.725
10.78


708
ARG
NH1
43.385
38.316
19.382
11.53


709
ARG
NH2
42.642
37.281
21.300
10.00


710
ARG
H
48.857
35.623
22.040
20.00


711
ARG
HA
47.516
35.294
19.567
20.00


712
ARG
1HB
47.990
37.689
21.376
20.00


713
ARG
2HB
46.686
36.526
21.493
20.00


714
ARG
1HG
45.916
37.234
19.260
20.00


715
ARG
2HG
47.204
38.380
19.156
20.00


716
ARG
1HD
45.508
39.367
19.671
20.00


717
ARG
2HD
46.466
39.497
21.205
20.00


718
ARG
HE
44.748
38.186
22.399
20.00


719
ARG
1HH1
42.596
37.960
18.878
20.00


720
ARG
2HH1
44.085
38.855
18.925
20.00


721
ARG
1HH2
41.874
36.942
20.748
20.00


722
ARG
2HH2
42.724
37.024
22.270
20.00


723
TYR
N
50.170
37.367
19.339
12.06


724
TYR
CA
51.144
38.065
18.550
10.98


725
TYR
C
52.522
37.481
18.816
13.59


726
TYR
O
52.966
37.428
19.960
15.53


727
TYR
CB
51.220
39.576
18.875
9.94


728
TYR
CG
49.859
40.250
18.678
11.54


729
TYR
CD1
49.044
40.145
17.523
11.75


730
TYR
CD2
49.380
40.989
19.752
10.70


731
TYR
CE1
47.808
40.784
17.473
12.58


732
TYR
CE2
48.142
41.590
19.752
11.42


733
TYR
CZ
47.339
41.494
18.578
12.61


734
TYR
OH
46.051
41.986
18.423
13.20


735
TYR
H
50.266
37.312
20.329
20.00


736
TYR
HA
50.862
37.907
17.513
20.00


737
TYR
1HB
51.984
40.094
18.317
20.00


738
TYR
2HB
51.550
39.711
19.903
20.00


739
TYR
HD1
49.336
39.506
16.724
20.00


740
TYR
HD2
49.993
41.106
20.635
20.00


741
TYR
HE1
47.172
40.704
16.611
20.00


742
TYR
HE2
48.011
42.008
20.763
20.00


743
TYR
HH
45.857
42.735
18.985
20.00


744
ARG
N
53.153
37.103
17.699
13.40


745
ARG
CA
54.543
36.623
17.580
16.28


746
ARG
C
55.474
37.666
18.247
14.00


747
ARG
O
56.454
37.285
18.895
16.44


748
ARG
CB
54.915
36.428
16.068
17.48


749
ARG
CG
56.305
36.675
15.419
23.38


750
ARG
CD
56.316
37.199
13.926
28.56


751
ARG
NE
55.326
36.527
13.052
32.94


752
ARG
CZ
54.135
36.980
12.495
34.20


753
ARG
NH1
53.971
38.258
12.223
33.15


754
ARG
NH2
53.182
36.079
12.237
33.58


755
ARG
H
52.559
37.155
16.908
20.00


756
ARG
HA
54.579
35.718
18.147
20.00


757
ARG
1HB
54.506
35.533
15.621
20.00


758
ARG
2HB
54.611
37.441
15.734
20.00


759
ARG
1HG
56.835
37.432
16.015
20.00


760
ARG
2HG
56.937
35.799
15.540
20.00


761
ARG
1HD
56.210
38.289
13.888
20.00


762
ARG
2HD
57.315
36.970
13.512
20.00


763
ARG
HE
55.560
35.563
12.998
20.00


764
ARG
1HH2
52.331
36.288
11.752
20.00


765
ARG
2HH2
53.301
35.150
12.559
20.00


766
ARG
1HH1
53.238
38.710
11.709
20.00


767
ARG
2HH1
54.784
38.793
12.502
20.00


768
ASP
N
55.116
38.934
18.094
12.94


769
ASP
CA
55.973
40.036
18.616
12.52


770
ASP
C
55.797
40.445
20.096
12.63


771
ASP
O
56.452
41.331
20.648
11.75


772
ASP
CB
55.837
41.278
17.706
13.44


773
ASP
CG
56.220
41.009
16.226
15.48


774
ASP
OD1
57.040
40.145
15.911
14.91


775
ASP
OD2
55.608
41.579
15.347
17.68


776
ASP
H
54.485
39.225
17.376
20.00


777
ASP
HA
56.988
39.663
18.528
20.00


778
ASP
1HB
56.501
42.075
18.023
20.00


779
ASP
2HB
54.831
41.662
17.752
20.00


780
VAL
N
54.876
39.733
20.803
12.12


781
VAL
CA
54.573
40.057
22.191
11.29


782
VAL
C
54.455
38.762
22.960
9.78


783
VAL
O
53.550
37.945
22.857
11.48


784
VAL
CB
53.595
41.270
22.522
16.11


785
VAL
CG1
52.686
41.008
23.691
15.44


786
VAL
CG2
53.024
42.155
21.436
14.33


787
VAL
H
54.326
39.100
20.257
20.00


788
VAL
HA
55.521
40.473
22.533
20.00


789
VAL
HB
54.260
42.006
22.986
20.00


790
VAL
1HG1
53.241
40.703
24.580
20.00


791
VAL
2HG1
51.975
40.213
23.479
20.00


792
VAL
3HG1
52.106
41.885
23.978
20.00


793
VAL
1HG2
52.256
41.649
20.862
20.00


794
VAL
2HG2
53.807
42.481
20.755
20.00


795
VAL
3HG2
52.569
43.058
21.839
20.00


796
SER
N
55.506
38.663
23.758
10.16


797
SER
CA
55.834
37.561
24.654
11.16


798
SER
C
56.196
38.081
26.070
9.64


799
SER
O
56.758
39.170
26.254
11.51


800
SER
CB
57.105
36.786
24.050
10.81


801
SER
OG
56.905
36.279
22.695
12.18


802
SER
H
56.131
39.440
23.769
20.00


803
SER
HA
54.941
36.921
24.712
20.00


804
SER
1HB
57.272
35.928
24.740
20.00


805
SER
2HB
58.081
37.304
24.285
20.00


806
SER
HG
56.412
36.740
21.950
20.00


807
PRO
N
55.880
37.202
27.077
8.67


808
PRO
CA
56.329
37.300
28.414
10.79


809
PRO
C
57.824
36.995
28.517
13.35


810
PRO
O
58.237
35.943
28.085
14.81


811
PRO
CB
55.432
36.259
29.103
10.00


812
PRO
CG
55.263
35.208
28.112
10.77


813
PRO
CD
55.042
36.035
26.923
9.16


814
PRO
HA
56.203
38.308
28.764
20.00


815
PRO
1HB
54.379
36.441
29.197
20.00


816
PRO
2HB
55.825
35.933
30.055
20.00


817
PRO
1HG
56.174
34.610
28.028
20.00


818
PRO
2HG
54.446
34.516
28.338
20.00


819
PRO
1HD
54.004
36.311
26.766
20.00


820
PRO
2HD
55.499
35.527
26.092
20.00


821
PHE
N
58.603
37.926
29.144
13.59


822
PHE
CA
59.917
37.512
29.662
12.71


823
PHE
C
59.764
36.228
30.513
12.31


824
PHE
O
58.819
36.148
31.282
12.68


825
PHE
CB
60.730
38.634
30.385
9.81


826
PHE
CG
60.773
39.907
29.668
10.06


827
PHE
CD1
61.171
39.952
28.332
9.58


828
PHE
CD2
60.557
41.099
30.342
9.41


829
PHE
CE1
61.489
41.196
27.800
10.26


830
PHE
CE2
60.848
42.337
29.786
10.02


831
PHE
CZ
61.354
42.399
28.543
8.64


832
PHE
H
58.157
38.782
29.377
20.00


833
PHE
HA
60.489
37.218
28.782
20.00


834
PHE
1HB
61.767
38.289
30.303
20.00


835
PHE
2HB
60.716
38.738
31.460
20.00


836
PHE
HD1
61.347
39.055
27.761
20.00


837
PHE
HD2
60.194
41.061
31.361
20.00


838
PHE
HE1
61.915
41.252
26.806
20.00


839
PHE
HE2
60.710
43.231
30.370
20.00


840
PHE
HZ
61.689
43.349
28.141
20.00


841
ASP
N
60.707
35.281
30.364
11.62


842
ASP
CA
60.799
34.068
31.244
12.07


843
ASP
C
60.796
34.428
32.811
12.27


844
ASP
O
60.121
33.789
33.631
15.21


845
ASP
CB
62.118
33.232
30.924
13.40


846
ASP
CG
62.097
32.558
29.567
14.25


847
ASP
OD1
60.970
32.119
29.186
15.72


848
ASP
OD2
63.206
32.476
28.952
12.79


849
ASP
H
61.362
35.357
29.624
20.00


850
ASP
HA
59.915
33.471
31.028
20.00


851
ASP
1HB
62.233
32.436
31.648
20.00


852
ASP
2HB
63.005
33.861
31.009
20.00


853
HIS
N
61.645
35.431
33.141
12.16


854
HIS
CA
61.906
35.743
34.515
12.71


855
HIS
C
60.622
36.197
35.245
13.92


856
HIS
O
60.428
35.970
36.418
15.61


857
HIS
CB
63.111
36.710
34.678
12.05


858
HIS
CG
62.763
38.170
34.481
10.80


859
HIS
ND1
62.180
38.950
35.412
11.89


860
HIS
CD2
63.026
38.996
33.393
10.89


861
HIS
CE1
62.091
40.203
34.920
9.38


862
HIS
NE2
62.587
40.256
33.707
11.30


863
HIS
H
62.189
35.808
32.392
20.00


864
HIS
HA
62.205
34.800
34.956
20.00


865
HIS
1HB
63.930
36.436
34.003
20.00


866
HIS
2HB
63.521
36.613
35.682
20.00


867
HIS
HD1
61.951
38.686
36.324
20.00


868
HIS
HD2
63.513
38.693
32.486
20.00


869
HIS
HE1
61.660
41.067
35.402
20.00


870
SER
N
59.723
36.834
34.519
13.43


871
SER
CA
58.552
37.448
35.230
12.13


872
SER
C
57.176
36.863
34.862
12.76


873
SER
O
56.104
37.349
35.336
13.37


874
SER
CB
58.525
38.196
34.846
10.16


875
SER
OG
58.653
39.016
33.381
10.34


876
SER
H
59.957
37.166
33.600
20.00


877
SER
HA
58.674
37.373
36.302
20.00


878
SER
1HB
59.441
39.363
35.292
20.00


879
SER
2HB
57.743
39.503
35.420
20.00


880
SER
HG
57.994
38.636
32.702
20.00


881
ARG
N
57.244
35.805
34.022
11.78


882
ARG
CA
55.939
35.373
33.508
13.97


883
ARG
C
55.153
34.605
34.601
13.85


884
ARG
O
55.744
33.997
35.513
11.86


885
ARG
CB
56.173
34.471
32.280
12.96


886
ARG
CG
56.702
33.069
32.654
13.81


887
ARG
CD
57.016
32.181
31.428
13.20


888
ARG
NE
57.632
30.888
31.874
14.78


889
ARG
CZ
57.094
29.687
32.079
15.00


890
ARG
NH1
55.822
29.488
31.874
11.82


891
ARG
NH2
57.838
28.727
32.565
17.64


892
ARG
H
58.122
35.460
33.703
20.00


893
ARG
HA
55.398
36.266
33.193
20.00


894
ARG
1HB
56.888
34.953
31.615
20.00


895
ARG
2HB
55.248
34.372
31.713
20.00


896
ARG
1HG
55.959
32.540
33.249
20.00


897
ARG
2HG
57.586
33.156
33.285
20.00


898
ARG
1HD
57.745
32.661
30.777
20.00


899
ARG
2HD
56.126
31.982
30.828
20.00


900
ARG
HE
58.614
30.885
32.076
20.00


901
ARG
1HH1
55.444
28.561
32.028
20.00


902
ARG
2HH1
55.229
30.225
31.600
20.00


903
ARG
1HH2
57.363
27.856
32.770
20.00


904
ARG
2HH2
58.819
28.824
32.735
20.00


905
ILE
N
53.823
34.541
34.371
14.21


906
ILE
CA
53.015
33.695
35.241
12.58


907
ILE
C
52.784
32.276
34.706
14.61


908
ILE
O
52.311
31.983
33.572
15.26


909
ILE
CB
51.692
34.404
35.385
13.58


910
ILE
CG1
51.914
35.909
35.670
13.29


911
ILE
CG2
50.687
33.768
36.382
13.64


912
ILE
CD1
51.819
36.312
37.125
13.30


913
ILE
H
53.450
35.070
33.611
20.00


914
ILE
HA
53.491
33.658
36.221
20.00


915
ILE
HB
51.217
34.358
34.405
20.00


916
ILE
1HG1
51.085
36.426
35.186
20.00


917
ILE
2HG1
52.780
36.386
35.222
20.00


918
ILE
1HG2
51.116
33.664
37.379
20.00


919
ILE
2HG2
50.394
32.762
36.074
20.00


920
ILE
3HG2
49.777
34.367
36.452
20.00


921
ILE
1HD1
52.673
35.943
37.695
20.00


922
ILE
2HD1
50.909
35.966
37.616
20.00


923
ILE
3HD1
51.834
37.400
37.195
20.00


924
LYS
N
53.090
31.420
35.677
15.82


925
LYS
CA
52.968
29.984
35.485
15.98


926
LYS
C
51.581
29.539
35.986
17.60


927
LYS
O
51.237
29.849
37.111
19.95


928
LYS
CB
54.154
29.264
36.206
17.28


929
LYS
CG
55.459
30.029
36.021
17.24


930
LYS
CD
56.580
29.154
36.468
22.81


931
LYS
CE
57.923
29.820
36.118
26.05


932
LYS
NZ
59.002
28.881
36.461
31.86


933
LYS
H
53.331
31.776
36.578
20.00


934
LYS
HA
53.041
29.782
34.419
20.00


935
LYS
1HB
54.240
28.241
35.827
20.00


936
LYS
2HB
53.945
29.180
37.272
20.00


937
LYS
1HG
55.449
30.949
36.604
20.00


938
LYS
2HG
55.572
30.305
34.972
20.00


939
LYS
1HD
56.527
28.185
35.965
20.00


940
LYS
2HD
56.506
28.962
37.538
20.00


941
LYS
1HE
58.051
30.780
36.631
20.00


942
LYS
2HE
57.975
30.045
35.049
20.00


943
LYS
1HZ
58.861
27.982
35.937
20.00


944
LYS
2HZ
58.998
28.698
37.481
20.00


945
LYS
3HZ
59.917
29.296
36.191
20.00


946
LEU
N
50.885
28.827
35.063
17.25


947
LEU
CA
49.701
28.023
35.305
18.29


948
LEU
C
50.164
26.889
36.218
20.34


949
LEU
O
51.156
26.241
35.911
19.70


950
LEU
CB
49.199
27.455
33.986
18.28


951
LEU
CG
48.053
28.245
33.290
18.66


952
LEU
CD1
47.989
27.995
31.755
17.13


953
LEU
CD2
47.828
29.708
33.707
14.98


954
LEU
H
51.364
28.759
34.195
20.00


955
LEU
HA
48.963
28.629
35.838
20.00


956
LEU
1HB
48.868
26.443
34.106
20.00


957
LEU
2HB
50.029
27.419
33.293
20.00


958
LEU
HG
47.157
27.754
33.671
20.00


959
LEU
1HD1
48.064
26.933
31.522
20.00


960
LEU
2HD1
48.811
28.517
31.259
20.00


961
LEU
3HD1
47.039
28.334
31.374
20.00


962
LEU
1HD2
48.762
30.260
33.691
20.00


963
LEU
2HD2
47.441
29.754
34.725
20.00


964
LEU
3HD2
47.112
30.213
33.062
20.00


965
HIS
N
49.467
26.676
37.346
22.86


966
HIS
CA
49.798
25.580
38.220
25.86


967
HIS
C
49.188
24.299
37.604
30.06


968
HIS
O
48.407
23.576
38.179
31.82


969
HIS
CB
49.207
25.838
39.607
26.12


970
HIS
CG
49.625
27.147
40.252
25.12


971
HIS
ND1
48.983
27.623
41.360
25.76


972
HIS
CD2
50.620
28.085
39.869
24.91


973
HIS
CE1
49.574
28.827
41.642
25.52


974
HIS
NE2
50.566
29.138
40.757
26.33


975
HIS
H
48.586
27.148
37.402
20.00


976
HIS
HA
50.880
25.472
38.282
20.00


977
HIS
1HB
49.461
25.018
40.278
20.00


978
HIS
2HB
48.122
25.837
39.553
20.00


979
HIS
HD1
48.204
27.201
41.765
20.00


980
HIS
HD2
51.269
27.996
39.010
20.00


981
HIS
HE1
49.292
29.465
42.470
20.00


982
GLN
N
49.608
23.987
36.392
32.94


983
GLN
CA
49.271
22.663
35.842
36.50


984
GLN
C
50.532
21.955
35.351
37.97


985
GLN
O
51.618
22.541
35.302
37.18


986
GLN
CB
48.147
22.806
34.854
37.95


987
GLN
CG
48.266
24.086
34.021
40.06


988
GLN
CD
47.360
23.885
32.822
44.06


989
GLN
OE1
47.592
22.903
32.119
46.49


990
GLN
NE2
46.323
24.719
32.620
41.49


991
GLN
H
50.243
24.612
35.941
20.00


992
GLN
HA
48.926
21.997
36.641
20.00


993
GLN
1HB
47.226
22.901
35.438
20.00


994
GLN
2HB
48.003
21.889
34.282
20.00


995
GLN
1HG
49.283
24.268
33.676
20.00


996
GLN
2HG
47.866
24.901
34.612
20.00


997
GLN
1HE2
45.658
24.510
31.912
20.00


998
GLN
2HE2
46.171
25.495
33.241
20.00


999
GLU
N
50.320
20.649
35.092
41.15


1000
GLU
CA
51.547
19.859
34.850
41.70


1001
GLU
C
51.834
19.728
33.311
39.31


1002
GLU
O
52.984
19.644
32.860
38.68


1003
GLU
CB
51.430
18.558
35.655
45.57


1004
GLU
CG
51.679
18.866
37.145
54.22


1005
GLU
CD
50.777
17.977
38.035
60.23


1006
GLU
OE1
49.587
18.325
38.117
63.36


1007
GLU
OE2
51.253
16.964
38.605
62.48


1008
GLU
H
49.451
20.221
35.343
20.00


1009
GLU
HA
52.415
20.380
35.254
20.00


1010
GLU
1HB
52.138
17.803
35.321
20.00


1011
GLU
2HB
50.436
18.128
35.508
20.00


1012
GLU
1HG
51.411
19.888
37.403
20.00


1013
GLU
2HG
52.719
18.720
37.428
20.00


1014
ASP
N
50.713
19.782
32.532
38.53


1015
ASP
CA
50.859
19.700
31.061
37.73


1016
ASP
C
51.793
20.877
30.583
33.50


1017
ASP
O
52.946
20.793
30.147
35.46


1018
ASP
CB
49.374
19.842
30.492
43.21


1019
ASP
CG
49.448
20.048
28.963
49.96


1020
ASP
OD1
50.358
19.411
28.396
53.55


1021
ASP
OD2
48.668
20.859
28.386
52.89


1022
ASP
H
49.807
19.888
32.924
20.00


1023
ASP
HA
51.321
18.751
30.761
20.00


1024
ASP
1HB
48.803
20.635
30.964
20.00


1025
ASP
2HB
48.830
18.915
30.646
20.00


1026
ASN
N
51.117
22.012
30.774
28.37


1027
ASN
CA
51.658
23.198
30.253
21.99


1028
ASN
C
51.272
24.281
31.204
20.24


1029
ASN
O
50.088
24.519
31.310
21.87


1030
ASN
CB
51.062
23.311
28.867
19.04


1031
ASN
CG
51.901
24.202
27.972
18.04


1032
ASN
OD1
52.747
24.954
28.409
19.25


1033
ASN
ND2
51.670
24.083
26.677
15.06


1034
ASN
H
50.148
21.879
30.992
20.00


1035
ASN
HA
52.742
23.147
30.225
20.00


1036
ASN
1HB
50.053
23.709
28.917
20.00


1037
ASN
2HB
50.976
22.339
28.367
20.00


1038
ASN
1HD2
52.136
24.800
26.133
20.00


1039
ASN
2HD2
51.105
23.357
26.296
20.00


1040
ASP
N
52.310
24.934
31.781
18.00


1041
ASP
CA
52.359
26.033
32.774
18.78


1042
ASP
C
52.269
27.339
32.022
17.35


1043
ASP
O
52.385
28.381
32.643
18.81


1044
ASP
CB
53.678
26.048
33.673
19.48


1045
ASP
CG
55.010
26.577
33.066
23.10


1046
ASP
OD1
55.075
26.798
31.865
24.35


1047
ASP
OD2
56.022
26.809
33.756
29.58


1048
ASP
H
53.213
24.652
31.479
20.00


1049
ASP
HA
51.485
25.929
33.416
20.00


1050
ASP
1HB
53.905
25.042
34.027
20.00


1051
ASP
2HB
53.466
26.618
34.583
20.00


1052
TYR
N
52.126
27.268
30.658
16.55


1053
TYR
CA
52.342
28.547
29.854
12.98


1054
TYR
C
51.059
29.382
29.617
12.27


1055
TYR
O
50.072
28.908
29.056
12.81


1056
TYR
CB
53.128
28.308
28.524
10.36


1057
TYR
CG
53.307
29.633
27.752
12.42


1058
TYR
CD1
54.305
30.529
28.104
10.55


1059
TYR
CD2
52.385
30.073
26.782
11.80


1060
TYR
CE1
54.386
31.783
27.545
11.79


1061
TYR
CE2
52.453
31.353
26.260
10.71


1062
TYR
CZ
53.524
32.198
26.591
9.67


1063
TYR
OH
53.938
33.401
26.004
10.99


1064
TYR
H
52.132
26.366
30.228
20.00


1065
TYR
HA
53.022
29.162
30.449
20.00


1066
TYR
1HB
52.598
27.575
27.914
20.00


1067
TYR
2HB
54.096
27.862
28.732
20.00


1068
TYR
HD1
55.008
30.232
28.857
20.00


1069
TYR
HD2
51.588
29.416
26.475
20.00


1070
TYR
HE1
55.198
32.442
27.833
20.00


1071
TYR
HE2
51.561
31.484
25.630
20.00


1072
TYR
HH
53.565
33.505
25.119
20.00


1073
ILE
N
51.111
30.653
30.018
13.06


1074
ILE
CA
50.146
31.725
29.683
12.41


1075
ILE
C
50.996
32.948
29.283
11.32


1076
ILE
O
52.043
33.149
29.862
12.19


1077
ILE
CB
49.059
32.003
30.788
12.98


1078
ILE
CG1
48.065
33.056
30.196
8.76


1079
ILE
CG2
49.639
32.315
32.217
10.91


1080
ILE
CD1
46.906
33.342
31.116
9.88


1081
ILE
H
51.869
30.910
30.612
20.00


1082
ILE
HA
49.636
31.400
28.775
20.00


1083
ILE
HB
48.500
31.076
30.889
20.00


1084
ILE
1HG1
47.659
32.732
29.240
20.00


1085
ILE
2HG1
48.584
33.993
30.018
20.00


1086
ILE
1HG2
50.271
33.197
32.211
20.00


1087
ILE
2HG2
50.242
31.487
32.577
20.00


1088
ILE
3HG2
48.844
32.475
32.935
20.00


1089
ILE
1HD1
47.243
33.841
32.021
20.00


1090
ILE
2HD1
46.420
32.423
31.431
20.00


1091
ILE
3HD1
46.150
33.978
30.654
20.00


1092
ASN
N
50.614
33.705
28.262
9.16


1093
ASN
CA
51.251
34.994
27.951
9.65


1094
ASN
C
50.836
36.013
28.977
10.37


1095
ASN
O
49.889
36.738
28.762
10.07


1096
ASN
CB
50.740
35.386
26.534
9.08


1097
ASN
CG
51.559
36.512
25.985
9.54


1098
ASN
OD1
51.733
37.578
26.614
10.96


1099
ASN
ND2
52.102
36.212
24.777
9.06


1100
ASN
H
49.891
33.381
27.666
20.00


1101
ASN
HA
52.326
34.865
28.001
20.00


1102
ASN
1HB
49.721
35.743
26.595
20.00


1103
ASN
2HB
50.681
34.548
25.844
20.00


1104
ASN
1HD2
52.677
36.857
24.276
20.00


1105
ASN
2HD2
51.947
35.294
24.398
20.00


1106
ALA
N
51.472
36.004
30.161
9.41


1107
ALA
CA
51.160
37.001
31.204
10.05


1108
ALA
C
52.418
37.231
31.951
11.58


1109
ALA
O
53.203
36.292
32.110
12.92


1110
ALA
CB
50.197
36.373
32.229
7.50


1111
ALA
H
52.104
35.256
30.340
20.00


1112
ALA
HA
50.721
37.888
30.752
20.00


1113
ALA
1HB
50.631
35.477
32.665
20.00


1114
ALA
2HB
49.277
36.060
31.754
20.00


1115
ALA
3HB
49.933
37.050
33.037
20.00


1116
SER
N
52.522
38.468
32.470
10.51


1117
SER
CA
53.663
38.902
33.299
11.23


1118
SER
C
53.285
39.621
34.550
10.85


1119
SER
O
52.423
40.474
34.557
12.48


1120
SER
CB
54.393
39.958
32.386
7.55


1121
SER
OG
54.544
39.424
30.979
10.45


1122
SER
H
51.738
39.068
32.307
20.00


1123
SER
HA
54.292
38.048
33.555
20.00


1124
SER
1HB
55.364
40.197
32.840
20.00


1125
SER
2HB
53.966
41.002
32.539
20.00


1126
SER
HG
53.779
38.963
30.539
20.00


1127
LEU
N
54.089
39.317
35.577
11.48


1128
LEU
CA
53.997
40.074
36.831
12.53


1129
LEU
C
54.875
41.328
36.773
13.15


1130
LEU
O
56.106
41.237
36.710
13.65


1131
LEU
CB
54.509
39.118
37.938
13.18


1132
LEU
CG
54.050
39.236
39.386
15.58


1133
LEU
CD1
53.078
40.321
39.819
15.45


1134
LEU
CD2
55.183
39.160
40.327
15.90


1135
LEU
H
54.798
38.633
35.444
20.00


1136
LEU
HA
52.955
40.335
37.005
20.00


1137
LEU
1HB
55.596
39.023
37.872
20.00


1138
LEU
2HB
54.181
38.124
37.632
20.00


1139
LEU
HG
53.486
38.316
39.575
20.00


1140
LEU
1HD1
52.149
40.243
39.258
20.00


1141
LEU
2HD1
53.486
41.319
39.654
20.00


1142
LEU
3HD1
52.812
40.238
40.873
20.00


1143
LEU
1HD2
55.856
39.996
40.139
20.00


1144
LEU
2HD2
55.743
38.233
40.214
20.00


1145
LEU
3HD2
54.838
39.213
41.361
20.00


1146
ILE
N
54.198
42.491
36.870
12.91


1147
ILE
CA
54.849
43.764
37.188
13.87


1148
ILE
C
54.768
44.035
38.703
16.47


1149
ILE
O
53.759
44.202
39.394
16.73


1150
ILE
CB
54.282
44.944
36.382
13.55


1151
ILE
CG1
54.385
44.786
34.837
12.82


1152
ILE
CG2
54.940
46.250
36.798
16.67


1153
ILE
CD1
54.103
43.394
34.279
12.75


1154
ILE
H
53.200
42.393
36.826
20.00


1155
ILE
HA
55.895
43.661
36.897
20.00


1156
ILE
HB
53.217
45.012
36.617
20.00


1157
ILE
1HG1
55.383
45.077
34.511
20.00


1158
ILE
2HG1
53.700
45.497
34.362
20.00


1159
ILE
1HG2
56.026
46.220
36.689
20.00


1160
ILE
2HG2
54.753
46.467
37.845
20.00


1161
ILE
3HG2
54.556
47.094
36.229
20.00


1162
ILE
1HD1
53.156
42.977
34.619
20.00


1163
ILE
2HD1
54.904
42.685
34.471
20.00


1164
ILE
3HD1
54.016
43.465
33.195
20.00


1165
LYS
N
55.961
44.052
39.204
16.38


1166
LYS
CA
56.155
44.186
40.594
19.03


1167
LYS
C
56.848
45.516
40.860
18.79


1168
LYS
O
58.065
45.591
40.884
18.39


1169
LYS
CB
56.939
42.956
40.929
24.89


1170
LYS
CG
56.912
42.866
42.439
36.70


1171
LYS
CD
57.328
41.533
43.051
45.35


1172
LYS
CE
57.186
41.692
44.560
49.89


1173
LYS
NZ
57.538
40.467
45.290
53.29


1174
LYS
H
56.745
43.962
38.586
20.00


1175
LYS
HA
55.199
44.202
41.123
20.00


1176
LYS
1HB
57.961
43.013
40.539
20.00


1177
LYS
2HB
56.467
42.081
40.482
20.00


1178
LYS
1HG
55.910
43.036
42.726
20.00


1179
LYS
2HG
57.473
43.692
42.872
20.00


1180
LYS
1HD
58.364
41.333
42.777
20.00


1181
LYS
2HD
56.711
40.725
42.648
20.00


1182
LYS
1HE
56.135
41.919
44.779
20.00


1183
LYS
2HE
57.770
42.540
44.932
20.00


1184
LYS
1HZ
58.555
40.282
45.176
20.00


1185
LYS
2HZ
57.015
39.665
44.873
20.00


1186
LYS
3HZ
57.314
40.520
46.304
20.00


1187
MET
N
56.027
46.567
41.062
17.44


1188
MET
CA
56.634
47.846
41.393
17.07


1189
MET
C
57.007
47.929
42.923
17.04


1190
MET
O
56.147
48.095
43.790
16.87


1191
MET
CB
55.675
48.907
40.957
15.46


1192
MET
CG
55.291
48.734
39.503
15.47


1193
MET
SD
56.753
48.529
38.450
16.71


1194
MET
CE
57.080
50.195
38.026
12.89


1195
MET
H
55.032
46.464
41.035
20.00


1196
MET
HA
57.546
47.951
40.808
20.00


1197
MET
1HB
56.133
49.884
41.087
20.00


1198
MET
2HB
54.772
48.927
41.568
20.00


1199
MET
1HG
54.709
49.588
39.160
20.00


1200
MET
2HG
54.618
47.892
39.385
20.00


1201
MET
1HE
57.389
50.721
38.923
20.00


1202
MET
2HE
56.172
50.653
37.664
20.00


1203
MET
3HE
57.869
50.255
37.283
20.00


1204
GLU
N
58.311
47.763
43.214
20.27


1205
GLU
CA
58.778
47.729
44.589
22.54


1206
GLU
C
58.455
49.032
45.367
22.33


1207
GLU
O
57.551
49.145
46.174
24.08


1208
GLU
CB
60.261
47.369
44.550
26.36


1209
GLU
CG
60.752
46.542
45.777
35.25


1210
GLU
CD
62.306
46.400
45.765
40.00


1211
GLU
OE1
63.007
47.377
46.070
43.15


1212
GLU
OE2
62.798
45.322
45.423
43.54


1213
GLU
H
58.846
47.524
42.399
20.00


1214
GLU
HA
58.235
46.912
45.065
20.00


1215
GLU
1HB
60.894
48.246
44.415
20.00


1216
GLU
2HB
60.457
46.747
43.675
20.00


1217
GLU
1HG
60.308
45.548
45.809
20.00


1218
GLU
2HG
60.494
47.045
46.708
20.00


1219
GLU
N
59.176
50.055
45.053
23.41


1220
GLU
CA
58.964
51.347
45.670
24.81


1221
GLU
C
57.479
51.755
45.865
24.74


1222
GLU
O
57.051
52.142
46.947
24.77


1223
GLU
CB
59.765
52.321
44.797
26.99


1224
GLU
CG
59.810
53.801
45.255
35.79


1225
GLU
CD
60.222
54.688
44.049
45.06


1226
GLU
OE1
59.969
54.335
42.876
48.32


1227
GLU
OE2
60.747
55.769
44.308
49.68


1228
GLU
H
59.978
49.853
44.499
20.00


1229
GLU
HA
59.422
51.306
46.657
20.00


1230
GLU
1HB
59.378
52.294
43.798
20.00


1231
GLU
2HB
60.779
51.944
44.681
20.00


1232
GLU
1HG
60.583
53.892
46.009
20.00


1233
GLU
2HG
58.858
54.133
45.660
20.00


1234
ALA
N
56.670
51.652
44.799
22.17


1235
ALA
CA
55.246
52.057
44.836
21.64


1236
ALA
C
54.539
51.006
45.549
22.46


1237
ALA
O
53.160
51.123
45.691
24.05


1238
ALA
CB
54.806
52.202
43.393
20.53


1239
ALA
H
57.053
51.248
43.967
20.00


1240
ALA
HA
55.174
53.008
45.366
20.00


1241
ALA
1HB
54.756
51.228
42.929
20.00


1242
ALA
2HB
55.522
52.775
42.815
20.00


1243
ALA
3HB
53.829
52.664
43.317
20.00


1244
GLN
N
55.030
49.944
45.995
23.74


1245
GLN
CA
54.391
48.860
46.644
27.80


1246
GLN
C
53.125
48.391
45.853
26.92


1247
GLN
O
52.149
47.989
46.495
27.71


1248
GLN
CB
54.140
49.267
48.138
32.88


1249
GLN
CG
55.326
49.006
49.110
40.36


1250
GLN
CD
55.212
47.532
49.760
47.19


1251
GLN
OE1
54.421
47.292
50.673
52.84


1252
GLN
NE2
56.012
46.546
49.265
46.59


1253
GLN
H
55.964
49.826
45.665
20.00


1254
GLN
HA
55.085
48.022
46.580
20.00


1255
GLN
1HB
53.282
48.717
48.513
20.00


1256
GLN
2HB
53.816
50.302
48.171
20.00


1257
GLN
1HG
55.368
49.735
49.918
20.00


1258
GLN
2HG
56.264
49.080
48.553
20.00


1259
GLN
1HE2
55.903
45.690
49.757
20.00


1260
GLN
2HE2
56.637
46.689
48.503
20.00


1261
ARG
N
53.166
48.361
44.464
23.43


1262
ARG
CA
52.057
47.713
43.751
18.91


1263
ARG
C
52.453
46.726
42.694
16.84


1264
ARG
O
53.318
47.057
41.916
17.96


1265
ARG
CB
51.320
48.807
43.076
18.58


1266
ARG
CG
50.098
48.257
42.395
16.36


1267
ARG
CD
49.034
49.322
42.305
17.70


1268
ARG
NE
48.208
49.346
43.527
17.29


1269
ARG
CZ
47.441
50.424
43.806
15.94


1270
ARG
NH1
47.297
51.403
42.891
13.68


1271
ARG
NH2
46.819
50.417
44.975
18.40


1272
ARG
H
54.018
48.616
44.002
20.00


1273
ARG
HA
51.427
47.185
44.462
20.00


1274
ARG
1HB
51.976
49.317
42.372
20.00


1275
ARG
2HB
51.053
49.558
43.825
20.00


1276
ARG
1HG
49.683
47.403
42.929
20.00


1277
ARG
2HG
50.353
47.899
41.397
20.00


1278
ARG
1HD
48.372
49.152
41.452
20.00


1279
ARG
2HD
49.446
50.319
42.247
20.00


1280
ARG
HE
48.258
48.588
44.171
20.00


1281
ARG
1HH1
46.755
52.223
43.004
20.00


1282
ARG
2HH1
47.752
51.289
41.992
20.00


1283
ARG
1HH2
46.269
51.202
45.245
20.00


1284
ARG
2HH2
46.898
49.595
45.539
20.00


1285
SER
N
51.766
45.572
42.683
13.82


1286
SER
CA
51.692
44.596
41.633
12.48


1287
SER
C
50.434
44.551
40.727
11.37


1288
SER
O
49.287
44.615
41.157
13.16


1289
SER
CB
51.817
43.113
42.100
12.86


1290
SER
OG
53.028
42.834
42.899
19.01


1291
SER
H
51.167
45.419
43.464
20.00


1292
SER
HA
52.523
44.871
41.005
20.00


1293
SER
1HB
51.950
42.559
41.136
20.00


1294
SER
2HB
50.804
42.672
42.377
20.00


1295
SER
HG
53.168
43.269
43.803
20.00


1296
TYR
N
50.787
44.235
39.430
11.99


1297
TYR
CA
49.732
44.002
38.418
10.12


1298
TYR
C
50.149
42.759
37.675
10.62


1299
TYR
O
51.329
42.534
37.602
11.32


1300
TYR
CB
49.562
45.151
37.368
10.39


1301
TYR
CG
49.764
46.542
37.950
10.08


1302
TYR
CD1
51.063
46.952
38.255
10.55


1303
TYR
CD2
48.695
47.416
38.159
10.53


1304
TYR
CE1
51.305
48.211
38.707
12.90


1305
TYR
CE2
48.895
48.689
38.649
12.10


1306
TYR
CZ
50.180
49.106
38.885
13.13


1307
TYR
OH
50.199
50.433
39.253
13.22


1308
TYR
H
51.751
44.131
39.179
20.00


1309
TYR
HA
48.782
43.799
38.924
20.00


1310
TYR
1HB
48.582
45.095
36.888
20.00


1311
TYR
2HB
50.285
45.040
36.555
20.00


1312
TYR
HD1
51.873
46.248
38.135
20.00


1313
TYR
HD2
47.680
47.117
37.910
20.00


1314
TYR
HE1
52.383
48.243
38.882
20.00


1315
TYR
HE2
48.058
49.352
38.782
20.00


1316
TYR
HH
50.979
50.728
39.691
20.00


1317
ILE
N
49.222
42.018
37.068
10.35


1318
ILE
CA
49.503
41.053
35.972
7.97


1319
ILE
C
49.087
41.676
34.586
9.78


1320
ILE
O
47.914
41.999
34.387
10.25


1321
ILE
CB
48.760
39.736
36.289
9.05


1322
ILE
CG1
49.269
39.172
37.681
10.20


1323
ILE
CG2
48.976
38.754
35.095
8.37


1324
ILE
CD1
48.737
37.834
38.236
8.33


1325
ILE
H
48.275
42.270
37.213
20.00


1326
ILE
HA
50.572
40.865
35.958
20.00


1327
ILE
HB
47.694
39.953
36.380
20.00


1328
ILE
1HG1
49.048
39.919
38.429
20.00


1329
ILE
2HG1
50.359
39.121
37.645
20.00


1330
ILE
1HG2
50.043
38.615
34.936
20.00


1331
ILE
2HG2
48.543
39.117
34.167
20.00


1332
ILE
3HG2
48.537
37.783
35.302
20.00


1333
ILE
1HD1
49.021
37.050
37.542
20.00


1334
ILE
2HD1
47.661
37.804
38.225
20.00


1335
ILE
3HD1
49.128
37.549
39.212
20.00


1336
LEU
N
50.086
41.866
33.670
8.73


1337
LEU
CA
49.787
42.333
32.269
8.66


1338
LEU
C
49.661
41.053
31.404
11.10


1339
LEU
O
50.565
40.223
31.418
12.49


1340
LEU
CB
50.852
43.343
31.645
9.65


1341
LEU
CG
50.557
44.804
32.004
10.58


1342
LEU
CD1
51.628
45.857
31.638
11.19


1343
LEU
CD2
50.324
44.924
33.515
12.47


1344
LEU
H
50.995
41.592
33.979
20.00


1345
LEU
HA
48.813
42.831
32.284
20.00


1346
LEU
1HB
50.867
43.235
30.561
20.00


1347
LEU
2HB
51.845
43.080
32.000
20.00


1348
LEU
HG
49.634
45.070
31.499
20.00


1349
LEU
1HD1
51.749
45.864
30.559
20.00


1350
LEU
2HD1
52.586
45.584
32.073
20.00


1351
LEU
3HD1
51.364
46.862
31.958
20.00


1352
LEU
1HD2
51.193
44.547
34.051
20.00


1353
LEU
2HD2
49.440
44.385
33.853
20.00


1354
LEU
3HD2
50.173
45.958
33.809
20.00


1355
THR
N
48.531
40.850
30.708
10.83


1356
THR
CA
48.266
39.641
29.888
8.06


1357
THR
C
47.699
40.039
28.466
9.10


1358
THR
O
47.222
41.124
28.225
8.53


1359
THR
CB
47.333
38.650
30.660
8.87


1360
THR
OG1
47.456
37.292
30.225
11.27


1361
THR
CG2
45.834
39.019
30.813
8.63


1362
THR
H
47.838
41.569
30.829
20.00


1363
THR
HA
49.265
39.242
29.728
20.00


1364
THR
HB
47.726
38.689
31.711
20.00


1365
THR
HG1
47.258
36.919
29.323
20.00


1366
THR
1HG2
45.238
39.174
29.907
20.00


1367
THR
2HG2
45.766
39.973
31.337
20.00


1368
THR
3HG2
45.335
38.315
31.484
20.00


1369
GLN
N
47.760
39.180
27.461
7.55


1370
GLN
CA
47.071
39.610
26.199
7.51


1371
GLN
C
45.534
39.436
26.344
8.15


1372
GLN
O
45.108
38.664
27.188
9.26


1373
GLN
CB
47.562
38.744
25.030
7.72


1374
GLN
CG
47.407
37.252
25.399
7.48


1375
GLN
CD
47.989
36.233
24.490
7.54


1376
GLN
OE1
47.581
35.092
24.452
13.65


1377
GLN
NE2
49.116
36.537
23.918
6.16


1378
GLN
H
48.093
38.257
27.639
20.00


1379
GLN
HA
47.281
40.663
25.990
20.00


1380
GLN
1HB
48.615
38.974
24.855
20.00


1381
GLN
2HB
47.022
38.964
24.104
20.00


1382
GLN
1HG
46.374
36.962
25.596
20.00


1383
GLN
2HG
47.973
37.052
26.297
20.00


1384
GLN
1HE2
49.523
35.662
23.730
20.00


1385
GLN
2HE2
49.492
37.437
23.695
20.00


1386
GLY
N
44.700
40.048
25.468
8.70


1387
GLY
CA
43.381
39.512
25.333
8.95


1388
GLY
C
43.447
37.969
25.067
10.89


1389
GLY
O
44.117
37.488
24.141
12.56


1390
GLY
H
45.110
40.695
24.840
20.00


1391
GLY
1HA
42.923
40.000
24.471
20.00


1392
GLY
2HA
42.825
39.769
26.226
20.00


1393
PRO
N
42.703
37.161
25.868
11.90


1394
PRO
CA
42.702
35.712
25.665
10.45


1395
PRO
C
42.336
35.222
24.206
12.59


1396
PRO
O
41.485
35.804
23.503
12.30


1397
PRO
CB
41.616
35.253
26.615
10.51


1398
PRO
CG
41.508
36.340
27.662
11.89


1399
PRO
CD
41.846
37.636
26.938
9.07


1400
PRO
HA
43.706
35.498
26.026
20.00


1401
PRO
1HB
41.830
34.304
27.113
20.00


1402
PRO
2HB
40.642
35.140
26.128
20.00


1403
PRO
1HG
40.578
36.362
28.234
20.00


1404
PRO
2HG
42.309
36.169
28.380
20.00


1405
PRO
1HD
42.340
38.326
27.629
20.00


1406
PRO
2HD
40.938
38.092
26.560
20.00


1407
LEU
N
42.979
34.139
23.738
13.19


1408
LEU
CA
42.570
33.451
22.471
14.02


1409
LEU
C
41.455
32.441
22.773
13.93


1410
LEU
O
41.173
32.179
23.932
12.95


1411
LEU
CB
43.705
32.668
21.783
13.39


1412
LEU
CG
44.875
33.411
21.125
14.69


1413
LEU
CD1
46.091
33.381
21.981
13.28


1414
LEU
CD2
44.589
34.682
20.356
12.21


1415
LEU
H
43.863
33.945
24.174
20.00


1416
LEU
HA
42.170
34.195
21.784
20.00


1417
LEU
1HB
43.310
32.178
20.906
20.00


1418
LEU
2HB
44.080
31.757
22.250
20.00


1419
LEU
HG
45.188
32.734
20.321
20.00


1420
LEU
1HD1
46.300
32.381
22.362
20.00


1421
LEU
2HD1
46.027
34.045
22.844
20.00


1422
LEU
3HD1
46.952
33.682
21.388
20.00


1423
LEU
1HD2
44.522
35.528
21.034
20.00


1424
LEU
2HD2
43.657
34.594
19.801
20.00


1425
LEU
3HD2
45.373
34.903
19.634
20.00


1426
PRO
N
40.810
31.845
21.721
16.81


1427
PRO
CA
39.625
31.072
21.951
17.34


1428
PRO
C
39.955
29.842
22.707
16.85


1429
PRO
O
39.063
29.280
23.267
18.24


1430
PRO
CB
39.185
30.662
20.513
17.12


1431
PRO
CG
39.775
31.705
19.619
19.47


1432
PRO
CD
41.112
31.934
20.286
16.45


1433
PRO
HA
38.865
31.652
22.479
20.00


1434
PRO
1HB
38.100
30.601
20.422
20.00


1435
PRO
2HB
39.579
29.685
20.211
20.00


1436
PRO
1HG
39.869
31.368
18.588
20.00


1437
PRO
2HG
39.170
32.614
19.648
20.00


1438
PRO
1HD
41.526
32.906
20.005
20.00


1439
PRO
2HD
41.807
31.143
19.988
20.00


1440
ASN
N
41.232
29.451
22.729
15.30


1441
ASN
CA
41.785
28.298
23.484
14.86


1442
ASN
C
42.556
28.687
24.770
15.36


1443
ASN
O
43.108
27.833
25.417
15.84


1444
ASN
CB
42.877
27.529
22.617
14.48


1445
ASN
CG
44.147
28.314
22.038
16.03


1446
ASN
OD1
44.043
29.255
21.263
19.68


1447
ASN
ND2
45.329
27.892
22.449
15.67


1448
ASN
H
41.818
29.895
22.060
20.00


1449
ASN
HA
40.954
27.643
23.757
20.00


1450
ASN
1HB
42.375
27.105
21.737
20.00


1451
ASN
2HB
43.249
26.672
23.187
20.00


1452
ASN
1HD2
46.001
28.521
22.054
20.00


1453
ASN
2HD2
45.568
27.139
23.052
20.00


1454
THR
N
42.650
29.978
25.133
15.02


1455
THR
CA
43.391
30.291
26.417
12.29


1456
THR
C
42.474
31.036
27.517
11.96


1457
THR
O
42.852
31.476
28.583
11.69


1458
THR
CB
44.719
31.008
26.014
10.87


1459
THR
OG1
44.565
32.343
25.555
10.92


1460
THR
CG2
45.584
30.273
25.027
10.49


1461
THR
H
42.262
30.664
24.515
20.00


1462
THR
HA
43.646
29.369
26.917
20.00


1463
THR
HB
45.361
30.992
26.941
20.00


1464
THR
HG1
43.754
32.671
25.107
20.00


1465
THR
1HG2
45.153
30.085
24.039
20.00


1466
THR
2HG2
45.915
29.312
25.408
20.00


1467
THR
3HG2
46.499
30.848
24.857
20.00


1468
CYS
N
41.161
31.075
27.244
14.04


1469
CYS
CA
40.171
31.667
28.138
14.17


1470
CYS
C
40.085
30.933
29.493
12.97


1471
CYS
O
39.963
31.492
30.591
13.90


1472
CYS
CB
38.786
31.617
27.536
13.16


1473
CYS
SG
38.550
32.838
26.281
15.24


1474
CYS
H
40.878
30.770
26.336
20.00


1475
CYS
HA
40.460
32.696
28.339
20.00


1476
CYS
1HB
38.031
31.820
28.305
20.00


1477
CYS
2HB
38.541
30.623
27.152
20.00


1478
CYS
HG
38.695
32.291
25.082
20.00


1479
GLY
N
40.243
29.645
29.298
13.25


1480
GLY
CA
40.387
28.785
30.429
14.11


1481
GLY
C
41.808
28.832
31.180
14.77


1482
GLY
O
41.877
28.613
32.340
15.71


1483
GLY
H
40.296
29.275
28.376
20.00


1484
GLY
1HA
40.315
27.866
29.861
20.00


1485
GLY
2HA
39.548
29.026
31.088
20.00


1486
HIS
N
42.939
29.144
30.573
15.04


1487
HIS
CA
44.200
29.473
31.244
13.49


1488
HIS
C
43.971
30.831
31.942
14.38


1489
HIS
O
44.520
31.190
32.974
15.19


1490
HIS
CB
45.303
29.659
30.149
12.89


1491
HIS
CG
45.443
28.449
29.222
14.63


1492
HIS
ND1
45.683
28.487
27.875
13.48


1493
HIS
CD2
45.237
27.096
29.517
16.55


1494
HIS
CE1
45.572
27.255
27.426
14.33


1495
HIS
NE2
45.317
26.382
28.410
15.87


1496
HIS
H
42.914
28.968
29.590
20.00


1497
HIS
HA
44.420
28.687
31.970
20.00


1498
HIS
1HB
46.257
29.992
30.558
20.00


1499
HIS
2HB
44.992
30.483
29.501
20.00


1500
HIS
HD1
45.880
29.274
27.336
20.00


1501
HIS
HD2
44.997
26.700
30.496
20.00


1502
HIS
HE1
45.646
26.975
26.381
20.00


1503
PHE
N
43.159
31.695
31.311
12.72


1504
PHE
CA
43.089
33.072
31.837
12.68


1505
PHE
C
42.415
33.006
33.201
13.22


1506
PHE
O
42.872
33.545
34.203
12.12


1507
PHE
CB
42.315
33.909
30.774
12.82


1508
PHE
CG
42.032
35.335
31.183
9.60


1509
PHE
CD1
40.875
35.627
31.879
8.18


1510
PHE
CD2
42.919
36.384
30.909
8.54


1511
PHE
CE1
40.653
36.859
32.368
11.79


1512
PHE
CE2
42.654
37.665
31.367
11.03


1513
PHE
CZ
41.535
37.845
32.118
10.70


1514
PHE
H
42.743
31.410
30.457
20.00


1515
PHE
HA
44.103
33.467
31.947
20.00


1516
PHE
1HB
41.355
33.453
30.563
20.00


1517
PHE
2HB
42.841
33.912
29.814
20.00


1518
PHE
HD1
40.158
34.849
32.083
20.00


1519
PHE
HD2
43.824
36.183
30.347
20.00


1520
PHE
HE1
39.765
37.060
32.953
20.00


1521
PHE
HE2
43.281
38.521
31.136
20.00


1522
PHE
HZ
41.317
38.835
32.490
20.00


1523
TRP
N
41.278
32.289
33.173
12.17


1524
TRP
CA
40.450
32.222
34.411
12.15


1525
TRP
C
41.113
31.433
35.595
12.77


1526
TRP
O
41.043
31.813
36.756
12.89


1527
TRP
CB
39.015
31.707
34.001
13.28


1528
TRP
CG
38.226
32.858
33.399
13.46


1529
TRP
CD1
37.724
32.964
32.065
13.99


1530
TRP
CD2
37.952
34.113
34.051
12.69


1531
TRP
NE1
37.180
34.195
31.900
13.76


1532
TRP
CE2
37.314
34.931
33.090
12.21


1533
TRP
CE3
38.279
34.589
35.303
11.54


1534
TRP
CZ2
36.958
36.217
33.415
11.49


1535
TRP
CZ3
37.922
35.900
35.617
12.46


1536
TRP
CH2
37.265
36.700
34.699
11.61


1537
TRP
H
40.911
31.965
32.302
20.00


1538
TRP
HA
40.399
33.239
34.783
20.00


1539
TRP
1HB
38.472
31.313
34.862
20.00


1540
TRP
2HB
39.104
30.873
33.295
20.00


1541
TRP
HD1
37.760
32.155
31.345
20.00


1542
TRP
HE1
36.707
34.474
31.085
20.00


1543
TRP
HE3
38.784
33.971
36.026
20.00


1544
TRP
HZ2
36.450
36.835
32.687
20.00


1545
TRP
HZ3
38.094
36.300
36.599
20.00


1546
TRP
HH2
36.986
37.699
34.976
20.00


1547
GLU
N
41.780
30.326
35.178
13.48


1548
GLU
CA
42.730
29.627
35.996
12.78


1549
GLU
C
43.768
30.566
36.534
13.54


1550
GLU
O
43.972
30.594
37.732
13.56


1551
GLU
CB
43.388
28.531
35.219
11.88


1552
GLU
CG
44.436
27.771
36.130
15.11


1553
GLU
CD
45.202
26.754
35.308
17.43


1554
GLU
OE1
44.936
26.639
34.112
19.12


1555
GLU
OE2
46.076
26.069
35.793
19.81


1556
GLU
H
41.624
30.031
34.237
20.00


1557
GLU
HA
42.211
29.204
36.855
20.00


1558
GLU
1HB
43.840
28.925
34.313
20.00


1559
GLU
2HB
42.624
27.820
34.904
20.00


1560
GLU
1HG
43.929
27.252
36.939
20.00


1561
GLU
2HG
45.161
28.434
36.597
20.00


1562
MET
N
44.363
31.442
35.736
11.71


1563
MET
CA
45.348
32.380
36.339
12.23


1564
MET
C
44.716
33.407
37.337
11.68


1565
MET
O
45.324
33.773
38.327
11.24


1566
MET
CB
46.127
33.111
35.218
9.82


1567
MET
CG
46.844
34.402
35.674
11.63


1568
MET
SD
47.623
35.297
34.348
15.04


1569
MET
CE
46.176
36.105
33.568
11.38


1570
MET
H
44.302
31.230
34.763
20.00


1571
MET
HA
46.042
31.771
36.918
20.00


1572
MET
1HB
45.456
33.358
34.395
20.00


1573
MET
2HB
46.859
32.430
34.785
20.00


1574
MET
1HG
47.575
34.147
36.441
20.00


1575
MET
2HG
46.154
35.105
36.154
20.00


1576
MET
1HE
45.659
36.709
34.305
20.00


1577
MET
2HE
45.493
35.347
33.206
20.00


1578
MET
3HE
46.520
36.723
32.753
20.00


1579
VAL
N
43.503
33.877
37.018
12.17


1580
VAL
CA
42.734
34.719
37.923
10.63


1581
VAL
C
42.543
33.925
39.336
13.77


1582
VAL
O
42.754
34.422
40.455
14.26


1583
VAL
CB
41.481
35.257
37.215
10.58


1584
VAL
CG1
41.931
36.174
36.095
8.22


1585
VAL
CG2
40.524
36.097
38.147
10.48


1586
VAL
H
43.171
33.627
36.109
20.00


1587
VAL
HA
43.374
35.574
38.158
20.00


1588
VAL
HB
40.927
34.414
36.800
20.00


1589
VAL
1HG1
42.614
35.675
35.400
20.00


1590
VAL
2HG1
42.457
37.043
36.488
20.00


1591
VAL
3HG1
41.073
36.507
35.505
20.00


1592
VAL
1HG2
41.087
36.909
38.606
20.00


1593
VAL
2HG2
40.113
35.494
38.956
20.00


1594
VAL
3HG2
39.722
36.595
37.623
20.00


1595
TRP
N
42.224
32.627
39.175
13.52


1596
TRP
CA
42.001
31.790
40.338
14.59


1597
TRP
C
43.264
31.610
41.155
15.04


1598
TRP
O
43.328
32.070
42.288
16.22


1599
TRP
CB
41.340
30.544
39.858
12.97


1600
TRP
CG
40.867
29.820
41.069
17.46


1601
TRP
CD1
41.606
28.897
41.786
21.61


1602
TRP
CD2
39.602
29.940
41.731
19.79


1603
TRP
NE1
40.899
28.456
42.861
23.85


1604
TRP
CE2
39.653
29.065
42.870
22.70


1605
TRP
CE3
38.464
30.605
41.428
21.09


1606
TRP
CZ2
38.576
28.895
43.700
21.76


1607
TRP
CZ3
37.360
30.412
42.267
21.15


1608
TRP
CH2
37.413
29.570
43.399
21.23


1609
TRP
H
42.074
32.302
38.246
20.00


1610
TRP
HA
41.294
32.332
40.966
20.00


1611
TRP
1HB
42.030
29.916
39.289
20.00


1612
TRP
2HB
40.487
30.754
39.199
20.00


1613
TRP
HD1
42.618
28.612
41.516
20.00


1614
TRP
HE1
41.220
27.834
43.554
20.00


1615
TRP
HE3
38.407
31.218
40.555
20.00


1616
TRP
HZ2
38.667
28.250
44.569
20.00


1617
TRP
HZ3
36.437
30.916
42.045
20.00


1618
TRP
HH2
36.555
29.455
44.032
20.00


1619
GLU
N
44.259
30.940
40.543
16.06


1620
GLU
CA
45.592
30.695
41.135
15.05


1621
GLU
C
46.223
31.929
41.826
16.50


1622
GLU
O
46.831
31.834
42.894
18.37


1623
GLU
CB
46.473
30.020
40.099
13.43


1624
GLU
CG
45.967
28.568
39.973
13.77


1625
GLU
CD
46.558
27.837
38.747
14.43


1626
GLU
OE1
47.458
28.382
38.119
15.87


1627
GLU
OE2
46.113
26.745
38.435
15.61


1628
GLU
H
44.114
30.564
39.620
20.00


1629
GLU
HA
45.422
29.979
41.932
20.00


1630
GLU
1HB
47.522
30.030
40.407
20.00


1631
GLU
2HB
46.364
30.567
39.152
20.00


1632
GLU
1HG
44.895
28.546
39.840
20.00


1633
GLU
2HG
46.191
27.991
40.858
20.00


1634
GLN
N
45.999
33.062
41.202
14.99


1635
GLN
CA
46.714
34.258
41.610
14.10


1636
GLN
C
45.841
35.103
42.496
14.79


1637
GLN
O
46.292
36.113
42.957
14.03


1638
GLN
CB
47.074
35.107
40.341
13.84


1639
GLN
CG
48.001
34.423
39.298
14.77


1640
GLN
CD
49.291
33.960
40.073
20.12


1641
GLN
OE1
49.843
34.780
40.814
21.85


1642
GLN
NE2
49.740
32.664
39.964
18.11


1643
GLN
H
45.582
33.013
40.294
20.00


1644
GLN
HA
47.620
34.012
42.178
20.00


1645
GLN
1HB
47.560
36.034
40.653
20.00


1646
GLN
2HB
46.157
35.450
39.856
20.00


1647
GLN
1HG
48.269
35.110
38.493
20.00


1648
GLN
2HG
47.536
33.553
38.850
20.00


1649
GLN
1HE2
50.530
32.405
40.514
20.00


1650
GLN
2HE2
49.411
31.946
39.364
20.00


1651
LYS
N
44.583
34.682
42.756
14.24


1652
LYS
CA
43.720
35.355
43.752
15.01


1653
LYS
C
43.390
36.821
43.456
12.96


1654
LYS
O
43.245
37.665
44.331
13.31


1655
LYS
CB
44.218
35.116
45.226
19.21


1656
LYS
CG
44.427
33.587
45.521
21.85


1657
LYS
CD
44.580
33.241
47.008
29.47


1658
LYS
CE
45.043
31.802
47.295
31.82


1659
LYS
NZ
46.358
31.625
46.658
37.86


1660
LYS
H
44.246
33.917
42.208
20.00


1661
LYS
HA
42.775
34.834
43.635
20.00


1662
LYS
1HB
43.461
35.509
45.903
20.00


1663
LYS
2HB
45.135
35.675
45.430
20.00


1664
LYS
1HG
45.269
33.231
44.929
20.00


1665
LYS
2HG
43.538
33.081
45.155
20.00


1666
LYS
1HD
43.644
33.429
47.532
20.00


1667
LYS
2HD
45.293
33.928
47.452
20.00


1668
LYS
1HE
44.353
31.026
46.952
20.00


1669
LYS
2HE
45.156
31.662
48.378
20.00


1670
LYS
1HZ
47.041
32.309
47.036
20.00


1671
LYS
2HZ
46.295
31.809
45.636
20.00


1672
LYS
3HZ
46.730
30.665
46.798
20.00


1673
SER
N
43.292
37.085
42.172
14.72


1674
SER
CA
42.944
38.424
41.776
14.22


1675
SER
C
41.469
38.644
41.990
15.12


1676
SER
O
40.653
37.731
41.873
14.48


1677
SER
CB
43.222
38.649
40.258
12.78


1678
SER
OG
44.599
38.384
39.786
13.54


1679
SER
H
43.501
36.368
41.511
20.00


1680
SER
HA
43.424
39.132
42.463
20.00


1681
SER
1HB
42.684
39.566
39.862
20.00


1682
SER
2HB
42.553
37.916
39.760
20.00


1683
SER
HG
45.445
38.774
40.181
20.00


1684
ARG
N
41.194
39.943
42.269
13.87


1685
ARG
CA
39.838
40.374
42.565
14.62


1686
ARG
C
39.210
41.125
41.397
14.77


1687
ARG
O
38.037
41.061
41.111
13.72


1688
ARG
CB
39.935
41.251
43.846
14.39


1689
ARG
CG
38.548
41.299
44.523
23.02


1690
ARG
CD
37.577
42.376
44.071
27.49


1691
ARG
NE
36.501
42.588
45.040
30.20


1692
ARG
CZ
35.270
42.112
45.005
29.90


1693
ARG
NH1
34.915
40.949
44.459
31.36


1694
ARG
NH2
34.360
42.901
45.542
30.49


1695
ARG
H
41.983
40.543
42.411
20.00


1696
ARG
HA
39.228
39.487
42.741
20.00


1697
ARG
1HB
40.353
42.237
43.656
20.00


1698
ARG
2HB
40.624
40.744
44.518
20.00


1699
ARG
1HG
38.665
41.371
45.589
20.00


1700
ARG
2HG
38.050
40.344
44.361
20.00


1701
ARG
1HD
37.164
42.250
43.068
20.00


1702
ARG
2HD
38.127
43.313
44.077
20.00


1703
ARG
HE
36.646
43.361
45.657
20.00


1704
ARG
1HH1
33.929
40.756
44.381
20.00


1705
ARG
2HH1
35.573
40.273
44.127
20.00


1706
ARG
1HH2
33.407
42.577
45.455
20.00


1707
ARG
2HH2
34.560
43.766
45.978
20.00


1708
GLY
N
40.103
41.883
40.761
15.17


1709
GLY
CA
39.769
42.723
39.598
13.10


1710
GLY
C
40.451
42.232
38.273
12.93


1711
GLY
O
41.570
41.712
38.267
12.18


1712
GLY
H
41.036
41.839
41.124
20.00


1713
GLY
1HA
40.096
43.738
39.816
20.00


1714
GLY
2HA
38.686
42.743
39.482
20.00


1715
VAL
N
39.674
42.483
37.168
13.38


1716
VAL
CA
40.227
42.427
35.793
10.87


1717
VAL
C
39.995
43.725
35.172
9.66


1718
VAL
O
38.888
44.245
35.106
10.04


1719
VAL
CB
39.570
41.284
34.982
10.73


1720
VAL
CG1
39.639
39.894
35.612
11.72


1721
VAL
CG2
40.122
41.100
33.537
10.72


1722
VAL
H
38.722
42.761
37.332
20.00


1723
VAL
HA
41.295
42.251
35.853
20.00


1724
VAL
HB
38.516
41.544
34.929
20.00


1725
VAL
1HG1
39.229
39.859
36.619
20.00


1726
VAL
2HG1
40.675
39.558
35.682
20.00


1727
VAL
3HG1
39.100
39.172
34.999
20.00


1728
VAL
1HG2
41.197
40.918
33.522
20.00


1729
VAL
2HG2
39.948
41.984
32.925
20.00


1730
VAL
3HG2
39.637
40.265
33.032
20.00


1731
VAL
N
41.057
44.256
34.606
8.51


1732
VAL
CA
40.949
45.502
33.785
7.91


1733
VAL
C
41.098
45.261
32.275
8.39


1734
VAL
O
42.171
44.892
31.831
9.71


1735
VAL
CB
41.905
46.631
34.279
6.14


1736
VAL
CG1
41.684
47.022
35.734
7.70


1737
VAL
CG2
41.778
47.812
33.395
6.32


1738
VAL
H
41.884
43.822
34.895
20.00


1739
VAL
HA
39.938
45.889
33.912
20.00


1740
VAL
HB
42.928
46.278
34.202
20.00


1741
VAL
1HG1
41.809
46.162
36.389
20.00


1742
VAL
2HG1
40.681
47.425
35.882
20.00


1743
VAL
3HG1
42.394
47.791
36.054
20.00


1744
VAL
1HG2
40.751
48.182
33.347
20.00


1745
VAL
2HG2
42.150
47.616
32.391
20.00


1746
VAL
3HG2
42.380
48.634
33.780
20.00


1747
MET
N
40.029
45.551
31.499
8.82


1748
MET
CA
40.098
45.371
30.025
8.53


1749
MET
C
40.050
46.649
29.219
9.29


1750
MET
O
39.015
47.259
29.225
9.66


1751
MET
CB
38.784
44.680
29.671
8.63


1752
MET
CG
38.641
44.332
28.205
9.02


1753
MET
SD
37.443
43.055
27.893
13.59


1754
MET
CE
37.600
42.908
26.065
7.30


1755
MET
H
39.197
45.854
31.962
20.00


1756
MET
HA
40.941
44.743
29.751
20.00


1757
MET
1HB
37.913
45.199
30.067
20.00


1758
MET
2HB
38.900
43.841
30.315
20.00


1759
MET
1HG
39.586
43.983
27.797
20.00


1760
MET
2HG
38.320
45.209
27.645
20.00


1761
MET
1HE
38.649
42.746
25.840
20.00


1762
MET
2HE
37.313
43.833
25.576
20.00


1763
MET
3HE
37.023
42.066
25.702
20.00


1764
LEU
N
41.108
47.023
28.523
8.05


1765
LEU
CA
41.161
48.369
27.911
6.79


1766
LEU
C
40.878
48.480
26.338
8.29


1767
LEU
O
41.027
49.534
25.740
8.17


1768
LEU
CB
42.531
48.968
28.277
8.82


1769
LEU
CG
42.851
48.939
29.793
9.33


1770
LEU
CD1
41.825
49.803
30.601
6.68


1771
LEU
CD2
44.286
49.352
29.927
8.69


1772
LEU
H
41.914
46.450
28.660
20.00


1773
LEU
HA
40.405
48.977
28.396
20.00


1774
LEU
1HB
42.648
49.982
27.900
20.00


1775
LEU
2HB
43.278
48.364
27.763
20.00


1776
LEU
HG
42.807
47.915
30.157
20.00


1777
LEU
1HD1
40.826
49.357
30.594
20.00


1778
LEU
2HD1
41.756
50.793
30.148
20.00


1779
LEU
3HD1
42.127
49.940
31.640
20.00


1780
LEU
1HD2
44.381
50.415
29.708
20.00


1781
LEU
2HD2
44.933
48.881
29.208
20.00


1782
LEU
3HD2
44.686
49.148
30.922
20.00


1783
ASN
N
40.414
47.337
25.761
8.85


1784
ASN
CA
40.131
47.123
24.392
10.85


1785
ASN
C
38.659
46.635
24.231
10.96


1786
ASN
O
38.021
46.324
25.247
11.52


1787
ASN
CB
41.197
46.126
23.941
10.56


1788
ASN
CG
40.890
44.664
24.261
10.18


1789
ASN
OD1
40.432
43.836
23.484
13.30


1790
ASN
ND2
41.203
44.346
25.480
6.84


1791
ASN
H
39.979
46.747
26.435
20.00


1792
ASN
HA
40.182
48.082
23.880
20.00


1793
ASN
1HB
42.177
46.387
24.344
20.00


1794
ASN
2HB
41.276
46.154
22.858
20.00


1795
ASN
1HD2
41.057
43.367
25.597
20.00


1796
ASN
2HD2
41.445
44.908
26.261
20.00


1797
ARG
N
38.180
46.553
22.953
12.81


1798
ARG
CA
36.927
45.848
22.626
12.84


1799
ARG
C
37.350
44.502
22.051
13.06


1800
ARG
O
38.503
44.343
21.679
13.72


1801
ARG
CB
35.917
46.694
21.830
15.06


1802
ARG
CG
35.700
48.081
22.459
23.73


1803
ARG
CD
34.608
48.863
21.755
34.40


1804
ARG
NE
34.599
48.708
20.298
44.56


1805
ARG
CZ
35.344
49.461
19.525
51.42


1806
ARG
NH1
36.112
50.366
20.022
54.99


1807
ARG
NH2
35.346
49.337
18.230
53.99


1808
ARG
H
38.768
46.870
22.206
20.00


1809
ARG
HA
36.453
45.621
23.579
20.00


1810
ARG
1HB
34.965
46.180
21.772
20.00


1811
ARG
2HB
36.260
46.803
20.803
20.00


1812
ARG
1HG
36.626
48.660
22.436
20.00


1813
ARG
2HG
35.439
47.990
23.514
20.00


1814
ARG
1HD
34.562
49.917
22.003
20.00


1815
ARG
2HD
33.643
48.479
22.083
20.00


1816
ARG
HE
34.015
48.023
19.871
20.00


1817
ARG
1HH1
36.646
50.991
19.465
20.00


1818
ARG
2HH1
36.185
50.455
21.013
20.00


1819
ARG
1HH2
35.928
49.944
17.707
20.00


1820
ARG
2HH2
34.791
48.643
17.775
20.00


1821
VAL
N
36.412
43.522
22.089
13.43


1822
VAL
CA
36.678
42.221
21.443
16.12


1823
VAL
C
36.936
42.341
19.861
16.48


1824
VAL
O
37.508
41.501
19.204
14.56


1825
VAL
CB
35.416
41.364
21.767
14.79


1826
VAL
CG1
35.507
40.697
23.158
14.80


1827
VAL
CG2
35.222
40.300
20.662
16.58


1828
VAL
H
35.544
43.637
22.538
20.00


1829
VAL
HA
37.574
41.806
21.888
20.00


1830
VAL
HB
34.531
42.004
21.742
20.00


1831
VAL
1HG1
35.515
41.454
23.937
20.00


1832
VAL
2HG1
36.431
40.123
23.260
20.00


1833
VAL
3HG1
34.687
40.009
23.336
20.00


1834
VAL
1HG2
36.123
39.694
20.523
20.00


1835
VAL
2HG2
34.966
40.732
19.690
20.00


1836
VAL
3HG2
34.404
39.618
20.907
20.00


1837
MET
N
36.406
43.407
19.280
17.62


1838
MET
CA
36.626
43.711
17.914
19.41


1839
MET
C
36.901
45.186
17.748
17.22


1840
MET
O
36.164
46.011
18.235
16.41


1841
MET
CB
35.353
43.277
17.172
22.53


1842
MET
CG
35.669
43.239
15.645
30.44


1843
MET
SD
34.456
42.296
14.726
36.43


1844
MET
CE
33.433
43.769
14.332
32.23


1845
MET
H
35.921
44.042
19.872
20.00


1846
MET
HA
37.494
43.147
17.583
20.00


1847
MET
1HB
34.536
43.972
17.357
20.00


1848
MET
2HB
35.027
42.298
17.516
20.00


1849
MET
1HG
36.598
42.694
15.471
20.00


1850
MET
2HG
35.835
44.229
15.216
20.00


1851
MET
1HE
34.049
44.530
13.845
20.00


1852
MET
2HE
33.035
44.226
15.235
20.00


1853
MET
3HE
32.615
43.541
13.649
20.00


1854
GLU
N
37.970
45.511
17.065
17.49


1855
GLU
CA
38.300
46.936
16.903
18.64


1856
GLU
C
38.818
47.158
15.437
17.88


1857
GLU
O
39.395
46.229
14.856
18.32


1858
GLU
CB
39.271
47.483
17.997
16.54


1859
GLU
CG
39.163
46.802
19.374
16.82


1860
GLU
CD
40.244
47.335
20.294
15.94


1861
GLU
OE1
41.417
47.016
20.261
15.52


1862
GLU
OE2
39.878
48.107
21.133
15.98


1863
GLU
H
38.603
44.799
16.761
20.00


1864
GLU
HA
37.372
47.509
16.964
20.00


1865
GLU
1HB
39.171
48.563
18.106
20.00


1866
GLU
2HB
40.290
47.331
17.643
20.00


1867
GLU
1HG
39.267
45.731
19.339
20.00


1868
GLU
2HG
38.189
47.010
19.799
20.00


1869
LYS
N
38.446
48.382
14.874
19.17


1870
LYS
CA
38.777
48.777
13.484
20.14


1871
LYS
C
38.520
47.522
12.524
18.74


1872
LYS
O
39.311
47.173
11.670
18.86


1873
LYS
CB
40.278
49.240
13.415
21.50


1874
LYS
CG
40.703
50.654
13.986
24.11


1875
LYS
CD
42.172
50.552
14.578
28.82


1876
LYS
CE
43.021
51.809
14.894
30.30


1877
LYS
NZ
42.319
53.111
14.983
32.58


1878
LYS
H
37.978
49.029
15.463
20.00


1879
LYS
HA
38.115
49.580
13.155
20.00


1880
LYS
1HB
40.638
49.186
12.388
20.00


1881
LYS
2HB
40.863
48.468
13.917
20.00


1882
LYS
1HG
40.032
50.973
14.782
20.00


1883
LYS
2HG
40.674
51.390
13.184
20.00


1884
LYS
1HD
42.764
49.942
13.889
20.00


1885
LYS
2HD
42.152
49.930
15.476
20.00


1886
LYS
1HE
43.736
51.897
14.065
20.00


1887
LYS
2HE
43.661
51.644
15.777
20.00


1888
LYS
1HZ
41.751
53.142
15.851
20.00


1889
LYS
2HZ
41.700
53.243
14.157
20.00


1890
LYS
3HZ
43.009
53.887
15.036
20.00


1891
GLY
N
37.431
46.797
12.782
18.79


1892
GLY
CA
37.164
45.601
11.983
17.83


1893
GLY
C
37.939
44.317
12.298
19.02


1894
GLY
O
37.645
43.318
11.675
18.80


1895
GLY
H
36.805
47.142
13.472
20.00


1896
GLY
1HA
37.364
48.858
10.936
20.00


1897
GLY
2HA
36.104
45.378
12.101
20.00


1898
SER
N
38.905
44.320
13.292
16.08


1899
SER
CA
39.607
43.056
13.660
17.76


1900
SER
C
39.296
42.486
15.005
16.07


1901
SER
O
38.995
43.233
15.902
15.80


1902
SER
CB
41.114
43.073
13.410
21.32


1903
SER
OG
41.466
43.211
11.962
29.95


1904
SER
H
39.281
45.222
13.434
20.00


1905
SER
HA
39.189
42.275
13.020
20.00


1906
SER
1HB
41.468
42.062
13.716
20.00


1907
SER
2HB
41.685
43.644
14.204
20.00


1908
SER
HG
41.217
43.991
11.368
20.00


1909
LEU
N
39.354
41.139
15.085
16.19


1910
LEU
CA
39.179
40.408
16.344
14.22


1911
LEU
C
40.426
40.584
17.073
14.90


1912
LEU
O
41.500
40.325
16.507
16.30


1913
LEU
CB
38.953
38.890
16.239
13.16


1914
LEU
CG
37.613
38.637
15.495
12.66


1915
LEU
CD1
36.379
39.491
16.079
15.43


1916
LEU
CD2
37.330
37.112
15.281
13.88


1917
LEU
H
39.542
40.665
14.226
20.00


1918
LEU
HA
38.395
40.914
16.899
20.00


1919
LEU
1HB
38.892
38.447
17.234
20.00


1920
LEU
2HB
39.763
38.405
15.689
20.00


1921
LEU
HG
39.743
39.052
14.496
20.00


1922
LEU
1HD1
36.551
40.564
16.142
20.00


1923
LEU
2HD1
36.136
39.140
17.085
20.00


1924
LEU
3HD1
35.484
39.341
15.469
20.00


1925
LEU
1HD2
37.257
36.579
16.225
20.00


1926
LEU
2HD2
38.130
36.677
14.681
20.00


1927
LEU
3HD2
36.393
36.951
14.742
20.00


1928
LYS
N
40.213
41.120
18.298
14.30


1929
LYS
CA
41.214
41.721
19.186
11.19


1930
LYS
C
41.424
40.990
20.578
10.51


1931
LYS
O
42.491
41.101
21.208
11.24


1932
LYS
CB
40.927
43.219
19.400
11.90


1933
LYS
CG
41.294
44.096
18.204
15.22


1934
LYS
CD
42.782
44.088
18.074
16.86


1935
LYS
CE
43.416
44.879
16.995
20.26


1936
LYS
NZ
44.866
44.759
17.227
18.45


1937
LYS
H
39.250
41.290
18.494
20.00


1938
LYS
HA
42.072
41.565
18.549
20.00


1939
LYS
1HB
41.453
43.590
20.273
20.00


1940
LYS
2HB
39.873
43.359
19.638
20.00


1941
LYS
1HG
40.989
45.121
18.373
20.00


1942
LYS
2HG
40.822
43.779
17.280
20.00


1943
LYS
1HD
43.048
43.070
17.823
20.00


1944
LYS
2HD
43.172
44.442
19.028
20.00


1945
LYS
1HE
43.122
45.933
17.063
20.00


1946
LYS
2HE
43.135
44.495
16.012
20.00


1947
LYS
1HZ
45.192
43.803
17.446
20.00


1948
LYS
2HZ
45.137
45.336
18.077
20.00


1949
LYS
3HZ
45.463
45.200
16.489
20.00


1950
CYS
N
40.378
40.163
20.958
10.35


1951
CYS
CA
40.307
39.378
22.205
10.12


1952
CYS
O
39.140
38.345
22.075
13.34


1953
CYS
O
38.199
38.571
21.322
13.61


1954
CYS
CB
39.998
40.335
23.357
13.04


1955
CYS
SG
39.948
39.653
25.023
11.06


1956
CYS
H
39.554
40.270
20.385
20.00


1957
CYS
HA
41.260
38.903
22.390
20.00


1958
CYS
1HB
39.044
40.818
23.189
20.00


1959
CYS
2HB
40.715
41.148
23.356
20.00


1960
CYS
HG
41.059
39.958
25.695
20.00


1961
ALA
N
39.220
37.197
22.807
11.84


1962
ALA
CA
38.076
36.310
22.861
11.47


1963
ALA
C
36.942
36.970
23.673
13.20


1964
ALA
O
37.135
37.777
24.550
10.87


1965
ALA
CB
38.542
34.974
23.518
9.90


1966
ALA
H
39.961
37.072
23.467
20.00


1967
ALA
HA
37.727
36.169
21.837
20.00


1968
ALA
1HB
38.943
35.142
24.518
20.00


1969
ALA
2HB
39.334
34.524
22.920
20.00


1970
ALA
3HB
37.722
34.257
23.606
20.00


1971
GLN
N
35.725
36.522
23.415
12.25


1972
GLN
CA
34.645
36.830
24.422
13.18


1973
GLN
C
34.789
35.908
25.674
13.71


1974
GLN
O
34.306
34.800
25.733
14.92


1975
GLN
CB
33.424
36.554
23.562
13.64


1976
GLN
CG
32.149
37.021
24.112
14.19


1977
GLN
CD
32.229
38.437
24.551
14.78


1978
GLN
OE1
32.151
38.741
25.725
20.52


1979
GLN
NE2
32.162
39.286
23.542
13.59


1980
GLN
H
35.602
35.916
22.635
20.00


1981
GLN
HA
34.723
37.882
24.718
20.00


1982
GLN
1HB
33.359
35.487
23.379
20.00


1983
GLN
2HB
33.554
37.017
22.589
20.00


1984
GLN
1HG
31.839
36.429
24.969
20.00


1985
GLN
2HG
31.338
36.929
23.379
20.00


1986
GLN
1HE2
31.885
40.195
23.842
20.00


1987
GLN
2HE2
32.304
39.058
22.593
20.00


1988
TYR
N
35.597
36.366
26.628
12.19


1989
TYR
CA
36.060
35.379
27.613
11.14


1990
TYR
C
35.168
35.400
28.882
10.72


1991
TYR
O
35.292
34.588
29.784
12.61


1992
TYR
CB
37.551
35.557
27.877
10.70


1993
TYR
CG
37.814
36.894
28.483
12.19


1994
TYR
CD1
37.736
37.113
29.882
10.21


1995
TYR
CD2
38.194
37.946
27.679
11.16


1996
TYR
CE1
38.060
38.311
30.487
12.37


1997
TYR
CE2
38.525
39.175
28.244
10.83


1998
TYR
CZ
38.452
39.353
29.637
11.09


1999
TYR
OH
38.741
40.615
30.127
11.70


2000
TYR
H
36.006
37.267
26.500
20.00


2001
TYR
HA
35.959
34.369
27.208
20.00


2002
TYR
1HB
38.106
35.477
26.945
20.00


2003
TYR
2HB
37.949
34.775
28.517
20.00


2004
TYR
HD1
37.433
36.298
30.508
20.00


2005
TYR
HD2
38.288
37.831
26.601
20.00


2006
TYR
HE1
38.028
38.353
31.577
20.00


2007
TYR
HE2
38.875
39.932
27.553
20.00


2008
TYR
HH
37.890
41.054
30.183
20.00


2009
TRP
N
34.243
36.345
28.877
11.94


2010
TRP
CA
33.260
36.444
29.897
12.84


2011
TRP
C
31.795
36.329
29.296
14.59


2012
TRP
O
31.599
36.587
28.134
14.57


2013
TRP
CB
33.665
37.712
30.717
12.85


2014
TRP
CG
33.087
38.918
30.092
13.65


2015
TRP
CD1
31.828
39.488
30.403
14.58


2016
TRP
CD2
33.657
39.662
29.006
12.43


2017
TRP
NE1
31.613
40.540
29.550
14.02


2018
TRP
CE2
32.726
40.705
28.701
12.63


2019
TRP
CE3
34.809
39.538
28.302
13.32


2020
TRP
CZ2
33.067
41.598
27.737
12.31


2021
TRP
CZ3
35.137
40.434
27.306
11.49


2022
TRP
CH2
34.278
41.483
27.035
14.96


2023
TRP
H
34.167
36.958
28.097
20.00


2024
TRP
HA
33.359
35.577
30.550
20.00


2025
TRP
1HB
34.750
37.815
30.805
20.00


2026
TRP
2HB
33.287
37.655
31.738
20.00


2027
TRP
HD1
31.145
39.100
31.149
20.00


2028
TRP
HE1
30.758
41.024
29.513
20.00


2029
TRP
HE3
35.482
38.710
28.515
20.00


2030
TRP
HZ2
32.368
42.385
27.492
20.00


2031
TRP
HZ3
36.048
40.298
26.745
20.00


2032
TRP
HH2
34.554
42.186
26.270
20.00


2033
PRO
N
30.771
35.903
30.090
16.00


2034
PRO
CA
29.379
35.863
29.628
15.76


2035
PRO
C
28.711
37.188
29.393
16.40


2036
PRO
O
28.872
38.116
30.195
18.51


2037
PRO
CB
28.648
35.085
30.686
12.06


2038
PRO
CG
29.535
35.324
31.918
15.79


2039
PRO
CD
30.937
35.297
31.426
15.75


2040
PRO
HA
29.331
35.310
28.691
20.00


2041
PRO
1HB
28.646
34.019
30.437
20.00


2042
PRO
2HB
27.601
35.373
30.852
20.00


2043
PRO
1HG
29.349
36.293
32.360
20.00


2044
PRO
2HG
29.365
34.566
32.684
20.00


2045
PRO
1HD
31.323
34.282
31.325
20.00


2046
PRO
2HD
31.591
35.885
32.067
20.00


2047
GLN
N
27.952
37.249
28.248
18.99


2048
GLN
CA
27.291
38.520
27.966
21.65


2049
GLN
C
25.891
38.588
28.499
22.14


2050
GLN
O
25.303
39.651
28.554
20.49


2051
GLN
CB
27.240
38.783
26.497
26.00


2052
GLN
CG
28.579
39.367
26.064
32.71


2053
GLN
CD
28.474
39.304
24.551
36.57


2054
GLN
OE1
28.270
38.247
23.966
35.28


2055
GLN
NE2
28.566
40.493
23.988
40.87


2056
GLN
H
28.103
36.536
27.563
20.00


2057
GLN
HA
27.828
39.333
28.450
20.00


2058
GLN
1HB
26.462
39.506
26.222
20.00


2059
GLN
2HB
27.001
37.849
25.971
20.00


2060
GLN
1HG
29.420
38.737
26.370
20.00


2061
GLN
2HG
28.769
40.372
26.438
20.00


2062
GLN
1HE2
28.441
40.574
23.007
20.00


2063
GLN
2HE2
28.815
41.241
24.593
20.00


2064
LYS
N
25.408
37.425
28.909
20.39


2065
LYS
CA
24.255
37.495
29.783
19.10


2066
LYS
C
24.218
36.437
30.788
16.46


2067
LYS
O
24.860
35.417
30.584
16.58


2068
LYS
CB
23.043
37.308
28.996
22.59


2069
LYS
CG
22.991
36.049
28.192
24.94


2070
LYS
CD
21.840
36.224
27.229
30.53


2071
LYS
CE
21.248
37.656
27.135
32.07


2072
LYS
NZ
19.951
37.638
26.450
40.14


2073
LYS
H
25.913
36.568
28.818
20.00


2074
LYS
HA
24.207
38.466
30.286
20.00


2075
LYS
1HB
23.084
38.211
28.385
20.00


2076
LYS
2HB
22.156
37.389
29.639
20.00


2077
LYS
1HG
22.886
35.151
28.800
20.00


2078
LYS
2HG
23.896
35.943
27.603
20.00


2079
LYS
1HD
21.052
35.524
27.493
20.00


2080
LYS
2HD
22.158
35.907
26.237
20.00


2081
LYS
1HE
21.938
38.332
26.616
20.00


2082
LYS
2HE
21.014
38.102
28.111
20.00


2083
LYS
1HZ
19.364
37.019
27.058
20.00


2084
LYS
2HZ
20.056
37.233
25.501
20.00


2085
LYS
3HZ
19.574
38.608
26.433
20.00


2086
GLU
N
23.400
36.776
31.841
15.88


2087
GLU
CA
23.136
36.118
33.111
15.37


2088
GLU
C
22.807
34.620
32.974
15.69


2089
GLU
O
23.432
33.804
33.626
13.68


2090
GLU
CB
22.083
36.964
33.900
16.72


2091
GLU
CG
22.625
38.280
34.481
14.29


2092
GLU
CD
22.320
39.420
33.579
18.80


2093
GLU
OE1
22.205
39.180
32.359
21.62


2094
GLU
OE2
22.216
40.551
34.077
21.27


2095
GLU
H
22.923
37.629
31.683
20.00


2096
GLU
HA
24.072
36.180
33.655
20.00


2097
GLU
1HB
21.726
36.367
34.740
20.00


2098
GLU
2HB
21.182
37.117
33.295
20.00


2099
GLU
1HG
23.692
38.268
34.620
20.00


2100
GLU
2HG
22.172
38.502
35.438
20.00


2101
GLU
N
21.816
34.259
32.125
18.42


2102
GLU
CA
21.276
32.842
31.945
20.95


2103
GLU
C
22.156
31.928
31.090
20.76


2104
GLU
O
21.994
30.705
31.057
20.49


2105
GLU
CB
19.952
32.834
31.234
20.78


2106
GLU
CG
19.309
34.201
31.354
25.93


2107
GLU
CD
19.642
35.143
30.246
25.99


2108
GLU
OE1
19.653
34.697
29.122
28.63


2109
GLU
OE2
19.906
36.310
30.524
25.53


2110
GLU
H
21.335
35.045
31.723
20.00


2111
GLU
HA
21.174
32.451
32.958
20.00


2112
GLU
1HB
19.298
32.082
31.685
20.00


2113
GLU
2HB
20.022
32.547
30.179
20.00


2114
GLU
1HG
19.417
34.671
32.332
20.00


2115
GLU
2HG
18.245
34.072
31.265
20.00


2116
LYS
N
23.111
32.603
30.414
21.38


2117
LYS
CA
24.125
31.842
29.692
21.50


2118
LYS
C
25.526
31.935
30.345
21.97


2119
LYS
O
26.347
32.738
29.892
22.57


2120
LYS
CB
24.088
32.258
28.172
22.92


2121
LYS
CG
22.714
31.845
27.594
27.23


2122
LYS
CD
22.552
31.376
26.144
35.59


2123
LYS
CE
23.728
30.467
25.664
43.39


2124
LYS
NZ
24.007
29.243
26.485
46.48


2125
LYS
H
23.100
33.602
30.448
20.00


2126
LYS
HA
23.905
30.779
29.750
20.00


2127
LYS
1HB
24.907
31.743
27.668
20.00


2128
LYS
2HB
24.269
33.331
28.039
20.00


2129
LYS
1HG
21.975
32.616
27.813
20.00


2130
LYS
2HG
22.353
30.996
28.180
20.00


2131
LYS
1HD
22.496
32.263
25.506
20.00


2132
LYS
2HD
21.598
30.867
26.006
20.00


2133
LYS
1HE
24.630
31.088
25.626
20.00


2134
LYS
2HE
23.573
30.193
24.616
20.00


2135
LYS
1HZ
23.210
28.580
26.409
20.00


2136
LYS
2HZ
24.158
29.477
27.490
20.00


2137
LYS
3HZ
24.854
28.748
26.137
20.00


2138
GLU
N
25.773
31.078
31.373
21.26


2139
GLU
CA
27.139
30.999
31.912
22.94


2140
GLU
C
28.092
30.064
31.083
21.77


2141
GLU
O
27.645
29.223
30.310
23.33


2142
GLU
CB
27.231
30.453
33.369
22.83


2143
GLU
CG
26.205
29.525
33.954
28.82


2144
GLU
CD
25.370
28.477
33.224
29.12


2145
GLU
OE1
25.536
27.271
33.488
33.37


2146
GLU
OE2
24.429
28.906
32.545
28.44


2147
GLU
H
25.059
30.466
31.701
20.00


2148
GLU
HA
27.582
31.996
31.877
20.00


2149
GLU
1HB
27.261
31.330
34.014
20.00


2150
GLU
2HB
28.206
30.000
33.571
20.00


2151
GLU
1HG
25.454
30.212
34.324
20.00


2152
GLU
2HG
26.595
29.090
34.874
20.00


2153
MET
N
29.391
30.275
31.312
18.83


2154
MET
CA
30.416
29.603
30.511
17.54


2155
MET
C
31.128
28.585
31.349
19.07


2156
MET
O
31.491
28.947
32.433
20.58


2157
MET
CB
31.427
30.660
30.153
16.27


2158
MET
CG
30.870
31.714
29.186
16.56


2159
MET
SD
32.137
32.886
28.710
19.88


2160
MET
CE
33.223
31.855
27.860
18.70


2161
MET
H
29.589
30.862
32.098
20.00


2162
MET
HA
29.978
29.130
29.625
20.00


2163
MET
1HB
32.321
30.175
29.762
20.00


2164
MET
2HB
31.744
31.163
31.066
20.00


2165
MET
1HG
30.026
32.258
29.604
20.00


2166
MET
2HG
30.521
31.214
28.283
20.00


2167
MET
1HE
32.744
31.511
26.943
20.00


2168
MET
2HE
33.506
30.974
28.415
20.00


2169
MET
3HE
34.117
32.425
27.610
20.00


2170
ILE
N
31.339
27.348
30.934
18.63


2171
ILE
CA
32.211
26.451
31.678
20.60


2172
ILE
C
33.493
28.318
30.901
20.37


2173
ILE
O
33.409
26.217
29.700
23.05


2174
ILE
CB
31.480
25.129
31.975
24.01


2175
ILE
CG1
30.423
25.362
33.119
25.81


2176
ILE
CG2
32.435
24.026
32.386
24.90


2177
ILE
CD1
29.015
25.092
32.627
27.88


2178
ILE
H
30.974
27.074
30.050
20.00


2179
ILE
HA
32.485
26.885
32.636
20.00


2180
ILE
HB
30.985
24.804
31.061
20.00


2181
ILE
1HG1
30.463
26.402
33.452
20.00


2182
ILE
2HG1
30.652
24.754
34.001
20.00


2183
ILE
1HG2
33.016
24.304
33.266
20.00


2184
ILE
2HG2
33.118
23.779
31.571
20.00


2185
ILE
3HG2
31.883
23.113
32.621
20.00


2186
ILE
1HD1
28.917
24.029
32.403
20.00


2187
ILE
2HD1
28.793
25.634
31.710
20.00


2188
ILE
3HD1
28.264
25.343
33.374
20.00


2189
PHE
N
34.683
26.352
31.568
19.97


2190
PHE
CA
35.937
26.121
30.909
18.46


2191
PHE
C
36.319
24.745
31.318
19.73


2192
PHE
O
36.707
24.506
32.444
18.94


2193
PHE
CB
36.932
27.287
31.208
16.35


2194
PHE
CG
36.422
28.683
31.025
14.87


2195
PHE
CD1
36.522
29.299
29.779
13.55


2196
PHE
CD2
35.733
29.310
32.097
16.14


2197
PHE
CE1
35.830
30.461
29.569
14.72


2198
PHE
CE2
35.066
30.492
31.858
14.63


2199
PHE
CZ
35.099
31.052
30.579
14.92


2200
PHE
H
34.651
26.525
32.549
20.00


2201
PHE
HA
35.764
26.097
29.830
20.00


2202
PHE
1HB
37.703
27.282
30.445
20.00


2203
PHE
2HB
37.090
27.353
32.285
20.00


2204
PHE
HD1
37.082
28.849
28.984
20.00


2205
PHE
HD2
35.695
28.842
33.075
20.00


2206
PHE
HE1
35.848
30.933
28.597
20.00


2207
PHE
HE2
34.533
30.984
32.644
20.00


2208
PHE
HZ
34.566
31.975
30.381
20.00


2209
GLU
N
36.121
23.790
30.412
23.42


2210
GLU
CA
36.337
22.339
30.733
27.04


2211
GLU
C
37.729
21.979
30.888
26.67


2212
GLU
O
38.100
21.211
31.739
27.77


2213
GLU
CB
35.728
21.345
29.766
32.84


2214
GLU
CG
34.183
21.469
29.799
43.59


2215
GLU
CD
33.519
20.760
28.583
52.36


2216
GLU
OE1
33.847
21.115
27.436
54.69


2217
GLU
OE2
32.681
19.880
28.790
55.07


2218
GLU
H
35.751
24.069
29.529
20.00


2219
GLU
HA
35.881
22.173
31.709
20.00


2220
GLU
1HB
35.996
20.309
30.011
20.00


2221
GLU
2HB
36.098
21.541
28.755
20.00


2222
GLU
1HG
33.904
22.517
29.697
20.00


2223
GLU
2HG
33.744
21.100
30.727
20.00


2224
ASP
N
38.560
22.594
30.081
25.27


2225
ASP
CA
39.984
22.349
30.299
24.77


2226
ASP
C
40.545
22.756
31.677
24.82


2227
ASP
O
41.386
22.063
32.189
26.69


2228
ASP
CB
40.679
23.052
29.135
25.87


2229
ASP
CG
40.734
24.550
29.259
28.11


2230
ASP
OD1
39.805
25.153
29.754
27.95


2231
ASP
OD2
41.734
25.112
28.924
30.09


2232
ASP
H
38.274
23.318
29.453
20.00


2233
ASP
HA
40.119
21.276
30.225
20.00


2234
ASP
1HB
40.199
22.776
28.195
20.00


2235
ASP
2HB
41.699
22.679
29.067
20.00


2236
THR
N
40.124
23.834
32.305
22.69


2237
THR
CA
40.690
24.144
33.672
20.10


2238
THR
C
39.585
23.979
34.752
20.10


2239
THR
O
39.768
24.233
35.885
20.15


2240
THR
CB
41.135
25.633
33.587
18.17


2241
THR
OG1
40.007
26.430
33.110
15.16


2242
THR
CG2
42.544
25.763
32.851
16.50


2243
THR
H
39.685
24.464
31.679
20.00


2244
THR
HA
41.531
23.510
33.937
20.00


2245
THR
HB
41.412
25.917
34.651
20.00


2246
THR
HG1
39.736
26.169
32.225
20.00


2247
THR
1HG2
42.651
25.408
31.820
20.00


2248
THR
2HG2
43.224
25.098
33.381
20.00


2249
THR
3HG2
42.971
26.751
32.905
20.00


2250
ASN
N
38.400
23.517
34.414
21.38


2251
ASN
CA
37.484
23.164
35.497
23.28


2252
ASN
C
36.941
24.311
36.323
23.35


2253
ASN
O
36.879
24.212
37.538
24.28


2254
ASN
CB
38.125
22.180
36.450
27.97


2255
ASN
CG
37.063
21.199
36.881
32.19


2256
ASN
OD1
36.007
21.054
36.300
34.42


2257
ASN
ND2
37.398
20.416
37.882
31.14


2258
ASN
H
38.197
23.360
33.445
20.00


2259
ASN
HA
36.637
22.771
34.958
20.00


2260
ASN
1HB
38.630
22.649
37.291
20.00


2261
ASN
2HB
38.876
21.572
35.956
20.00


2262
ASN
1HD2
36.827
19.614
38.005
20.00


2263
ASN
2HD2
38.154
20.743
38.435
20.00


2264
LEU
N
36.523
25.343
35.557
22.74


2265
LEU
CA
36.054
26.662
36.015
21.67


2266
LEU
C
34.666
26.976
35.433
20.94


2267
LEU
O
34.360
26.609
34.348
21.39


2268
LEU
CB
37.062
27.693
35.512
21.84


2269
LEU
CG
38.192
28.179
36.501
23.27


2270
LEU
CD1
39.526
28.185
35.755
17.13


2271
LEU
CD2
38.304
27.532
37.894
21.62


2272
LEU
H
36.596
25.109
34.588
20.00


2273
LEU
HA
35.977
26.636
37.101
20.00


2274
LEU
1HB
36.570
28.580
35.111
20.00


2275
LEU
2HB
37.540
27.261
34.632
20.00


2276
LEU
HG
37.973
29.219
36.721
20.00


2277
LEU
1HD1
39.471
28.735
34.816
20.00


2278
LEU
2HD1
39.850
27.168
35.542
20.00


2279
LEU
3HD1
40.281
28.627
36.394
20.00


2280
LEU
1HD2
38.454
26.455
37.798
20.00


2281
LEU
2HD2
37.409
27.696
38.497
20.00


2282
LEU
3HD2
39.149
27.916
38.459
20.00


2283
LYS
N
33.788
27.630
36.164
21.10


2284
LYS
CA
32.465
28.108
35.683
19.53


2285
LYS
C
32.490
29.604
35.894
18.34


2286
LYS
O
33.087
30.091
36.832
20.22


2287
LYS
CB
31.333
27.455
36.480
20.94


2288
LYS
CG
29.922
27.807
36.039
22.87


2289
LYS
CD
28.975
26.839
36.717
29.27


2290
LYS
CE
27.555
27.322
37.117
32.16


2291
LYS
NZ
27.241
26.588
38.379
36.84


2292
LYS
H
34.067
27.812
37.110
20.00


2293
LYS
HA
32.356
27.890
34.626
20.00


2294
LYS
1HB
31.418
27.687
37.535
20.00


2295
LYS
2HB
31.452
26.379
36.378
20.00


2296
LYS
1HG
29.776
27.833
34.960
20.00


2297
LYS
2HG
29.738
28.789
36.395
20.00


2298
LYS
1HD
29.460
26.460
37.618
20.00


2299
LYS
2HD
28.872
25.967
36.075
20.00


2300
LYS
1HE
26.811
27.141
36.334
20.00


2301
LYS
2HE
27.560
28.394
37.332
20.00


2302
LYS
1HZ
28.022
26.733
39.071
20.00


2303
LYS
2HZ
27.136
25.563
38.252
20.00


2304
LYS
3HZ
26.383
26.914
38.881
20.00


2305
LEU
N
31.850
30.299
35.029
16.41


2306
LEU
CA
31.816
31.744
35.238
16.41


2307
LEU
C
30.414
32.310
34.879
16.89


2308
LEU
O
29.861
31.985
33.848
16.71


2309
LEU
CB
32.856
32.320
34.286
15.09


2310
LEU
CG
33.093
33.868
34.349
13.98


2311
LEU
CD1
33.803
34.225
33.001
15.42


2312
LEU
CD2
33.869
34.360
35.697
16.75


2313
LEU
H
31.410
29.830
34.259
20.00


2314
LEU
HA
32.044
32.013
36.257
20.00


2315
LEU
1HB
32.580
32.030
33.270
20.00


2316
LEU
2HB
33.813
31.832
34.474
20.00


2317
LEU
HG
32.130
34.370
34.324
20.00


2318
LEU
1HD1
33.298
33.816
32.134
20.00


2319
LEU
2HD1
34.821
33.849
32.995
20.00


2320
LEU
3HD1
33.860
35.305
32.873
20.00


2321
LEU
1HD2
34.834
33.868
35.776
20.00


2322
LEU
2HD2
33.302
34.161
36.605
20.00


2323
LEU
3HD2
34.065
35.433
35.659
20.00


2324
THR
N
29.882
33.181
35.720
17.65


2325
THR
CA
28.551
33.725
35.460
17.51


2326
THR
C
28.621
35.167
35.480
16.95


2327
THR
O
29.498
35.674
36.178
16.10


2328
THR
CB
27.606
33.300
36.590
15.94


2329
THR
OG1
27.778
31.872
36.920
15.73


2330
THR
CG2
26.172
33.301
36.033
17.67


2331
THR
H
30.415
33.344
36.554
20.00


2332
THR
HA
28.182
33.409
34.478
20.00


2333
THR
HB
27.496
34.079
37.426
20.00


2334
THR
HG1
28.648
31.469
37.142
20.00


2335
THR
1HG2
26.077
32.678
35.147
20.00


2336
THR
2HG2
25.823
34.300
35.797
20.00


2337
THR
3HG2
25.480
32.889
36.770
20.00


2338
LEU
N
27.703
35.781
34.691
15.85


2339
LEU
CA
27.556
37.232
34.739
16.51


2340
LEU
C
26.532
37.558
35.906
19.83


2341
LEU
O
25.356
37.257
35.814
20.59


2342
LEU
CB
27.158
37.822
33.324
15.58


2343
LEU
CG
26.882
39.324
33.346
15.08


2344
LEU
CD1
26.057
39.756
32.155
13.12


2345
LEU
CD2
28.113
40.188
33.679
15.75


2346
LEU
H
27.076
35.205
34.167
20.00


2347
LEU
HA
28.523
37.660
35.002
20.00


2348
LEU
1HB
26.279
37.289
32.972
20.00


2349
LEU
2HB
27.913
37.649
32.569
20.00


2350
LEU
HG
26.189
39.498
34.166
20.00


2351
LEU
1HD1
25.097
39.241
32.130
20.00


2352
LEU
2HD1
26.577
39.583
31.213
20.00


2353
LEU
3HD1
25.853
40.827
32.198
20.00


2354
LEU
1HD2
28.892
40.010
32.953
20.00


2355
LEU
2HD2
28.512
39.992
34.673
20.00


2356
LEU
3HD2
27.865
41.249
33.638
20.00


2357
ILE
N
27.041
38.159
37.021
18.46


2358
ILE
CA
26.043
38.466
38.063
18.30


2359
ILE
C
25.345
39.750
37.757
18.81


2360
ILE
O
24.145
39.889
37.903
19.41


2361
ILE
CB
26.654
38.493
39.445
17.44


2362
ILE
CG1
27.314
37.152
39.761
16.16


2363
ILE
CG2
25.700
38.914
40.537
17.37


2364
ILE
CD1
26.469
35.848
39.622
15.26


2365
ILE
H
28.018
38.357
37.091
20.00


2366
ILE
HA
25.263
37.704
38.059
20.00


2367
ILE
HB
27.457
39.233
39.436
20.00


2368
ILE
1HG1
27.712
37.198
40.771
20.00


2369
ILE
2HG1
28.194
37.048
39.123
20.00


2370
ILE
1HG2
24.902
38.179
40.612
20.00


2371
ILE
2HG2
25.274
39.901
40.363
20.00


2372
ILE
3HG2
26.190
38.945
41.509
20.00


2373
ILE
1HD1
26.117
35.706
38.599
20.00


2374
ILE
2HD1
25.604
35.841
40.288
20.00


2375
ILE
3HD1
27.069
34.972
39.875
20.00


2376
SER
N
26.099
40.697
37.346
18.02


2377
SER
CA
25.432
41.954
36.914
19.40


2378
SER
C
26.370
42.826
36.013
21.38


2379
SER
O
27.551
42.619
36.115
22.64


2380
SER
CB
25.076
42.740
38.219
21.28


2381
SER
OG
26.035
43.743
38.695
24.51


2382
SER
H
27.087
40.552
37.291
20.00


2383
SER
HA
24.533
41.708
36.356
20.00


2384
SER
1HB
24.803
42.025
39.038
20.00


2385
SER
2HB
24.053
43.172
38.066
20.00


2386
SER
HG
26.904
43.995
38.253
20.00


2387
GLU
N
25.933
43.809
35.222
22.91


2388
GLU
CA
26.837
44.927
34.671
25.57


2389
GLU
C
26.217
46.306
34.923
25.11


2390
GLU
O
25.011
46.358
34.981
28.12


2391
GLU
CB
27.228
44.878
33.158
27.94


2392
GLU
CG
26.075
44.442
32.355
32.29


2393
GLU
CD
26.377
44.181
30.922
38.30


2394
GLU
OE1
27.547
44.144
30.531
43.02


2395
GLU
OE2
25.405
43.982
30.205
41.87


2396
GLU
H
24.982
43.809
34.916
20.00


2397
GLU
HA
27.770
44.930
35.236
20.00


2398
GLU
1HB
27.987
44.106
33.047
20.00


2399
GLU
2HB
27.650
45.808
32.773
20.00


2400
GLU
1HG
25.222
45.118
32.423
20.00


2401
GLU
2HG
25.745
43.467
32.706
20.00


2402
ASP
N
27.039
47.342
35.079
20.31


2403
ASP
CA
26.705
48.761
35.113
18.75


2404
ASP
C
27.443
49.451
33.921
19.30


2405
ASP
O
28.624
49.821
33.900
17.85


2406
ASP
CB
27.189
49.177
36.507
21.92


2407
ASP
CG
27.254
50.675
36.768
28.13


2408
ASP
OD1
26.258
51.344
36.462
28.01


2409
ASP
OD2
28.321
51.154
37.274
33.77


2410
ASP
H
28.005
47.105
35.158
20.00


2411
ASP
HA
25.624
48.883
35.026
20.00


2412
ASP
1HB
28.199
48.802
36.674
20.00


2413
ASP
2HB
26.569
48.727
37.282
20.00


2414
ILE
N
26.646
49.500
32.878
19.47


2415
ILE
CA
27.011
50.169
31.640
20.98


2416
ILE
C
26.884
51.689
31.756
22.51


2417
ILE
O
25.854
52.187
32.173
25.15


2418
ILE
CB
26.054
49.679
30.540
22.51


2419
ILE
CG1
26.166
48.190
30.336
22.32


2420
ILE
CG2
26.210
50.376
29.202
23.73


2421
ILE
CD1
25.344
47.693
29.157
22.61


2422
ILE
H
25.726
49.152
33.013
20.00


2423
ILE
HA
28.044
49.924
31.444
20.00


2424
ILE
HB
25.034
49.883
30.893
20.00


2425
ILE
1HG1
25.831
47.659
31.231
20.00


2426
ILE
2HG1
27.204
47.891
30.185
20.00


2427
ILE
1HG2
26.990
49.941
28.588
20.00


2428
ILE
2HG2
26.412
51.439
29.278
20.00


2429
ILE
3HG2
25.287
50.309
28.630
20.00


2430
ILE
1HD1
25.810
47.995
28.217
20.00


2431
ILE
2HD1
24.316
48.054
29.173
20.00


2432
ILE
3HD1
25.309
46.600
29.147
20.00


2433
LYS
N
27.927
52.396
31.334
21.11


2434
LYS
CA
28.007
53.844
31.411
20.45


2435
LYS
C
28.454
54.260
29.997
20.80


2436
LYS
O
28.625
53.399
29.162
22.26


2437
LYS
CB
29.094
54.210
32.440
22.37


2438
LYS
CG
28.926
53.803
33.916
25.62


2439
LYS
CD
28.269
54.939
34.702
29.83


2440
LYS
CE
27.931
54.725
36.183
33.05


2441
LYS
NZ
27.390
56.048
36.625
35.32


2442
LYS
H
28.708
51.893
30.963
20.00


2443
LYS
HA
27.026
54.274
31.645
20.00


2444
LYS
1HB
29.330
55.273
32.393
20.00


2445
LYS
2HB
30.013
53.731
32.121
20.00


2446
LYS
1HG
29.915
53.631
34.341
20.00


2447
LYS
2HG
28.387
52.862
34.018
20.00


2448
LYS
1HD
27.317
55.140
34.208
20.00


2449
LYS
2HD
28.840
55.855
34.583
20.00


2450
LYS
1HE
28.821
54.455
36.758
20.00


2451
LYS
2HE
27.183
53.930
36.298
20.00


2452
LYS
1HZ
26.728
56.433
35.914
20.00


2453
LYS
2HZ
28.153
56.770
36.673
20.00


2454
LYS
3HZ
26.891
56.014
37.524
20.00


2455
THR
N
28.665
55.518
29.676
19.82


2456
THR
CA
28.839
55.815
28.253
21.59


2457
THR
C
30.207
55.342
27.586
20.83


2458
THR
O
30.252
54.972
26.399
22.59


2459
THR
CB
28.731
57.347
28.048
24.13


2460
THR
OG1
29.994
57.972
28.523
24.73


2461
THR
CG2
27.406
57.828
28.730
30.44


2462
THR
H
28.394
56.233
30.314
20.00


2463
THR
HA
28.017
55.332
27.719
20.00


2464
THR
HB
28.524
57.312
26.923
20.00


2465
THR
HG1
30.033
58.957
28.697
20.00


2466
THR
1HG2
27.365
57.757
29.806
20.00


2467
THR
2HG2
26.606
57.179
28.402
20.00


2468
THR
3HG2
27.015
58.808
28.421
20.00


2469
TYR
N
31.305
55.374
28.446
17.73


2470
TYR
CA
32.678
55.061
27.957
15.97


2471
TYR
CA
33.341
53.758
28.591
15.46


2472
TYR
C
34.328
53.178
28.162
15.86


2473
TYR
CB
33.284
56.428
28.157
12.55


2474
TYR
CG
33.967
56.737
29.464
12.56


2475
TYR
CD1
33.364
57.603
30.382
14.70


2476
TYR
CD2
35.206
56.191
29.786
14.86


2477
TYR
CE1
33.908
57.950
31.591
15.48


2478
TYR
CE2
35.785
56.566
30.989
16.69


2479
TYR
CZ
35.129
57.413
31.908
16.96


2480
TYR
OH
35.664
57.737
33.129
15.71


2481
TYR
H
31.090
55.949
29.230
20.00


2482
TYR
HA
32.616
54.883
26.881
20.00


2483
TYR
1HB
32.511
57.176
28.055
20.00


2484
TYR
2HB
33.813
56.779
27.310
20.00


2485
TYR
HD1
32.439
58.052
30.168
20.00


2486
TYR
HD2
35.662
55.472
29.127
20.00


2487
TYR
HE1
33.342
58.642
32.206
20.00


2488
TYR
HE2
36.782
56.174
31.160
20.00


2489
TYR
HH
35.472
57.124
33.840
20.00


2490
TYR
N
32.720
53.248
29.650
14.74


2491
TYR
CA
33.167
52.050
30.352
14.03


2492
TYR
C
31.906
51.359
30.862
16.12


2493
TYR
O
30.824
51.930
30.915
17.82


2494
TYR
CB
34.251
52.412
31.375
12.74


2495
TYR
CG
33.728
53.134
32.579
15.40


2496
TYR
CD1
33.475
52.431
33.758
13.77


2497
TYR
CD2
33.476
54.490
32.544
18.58


2498
TYR
CE1
33.015
53.078
34.883
15.81


2499
TYR
CE2
32.944
55.161
33.649
17.84


2500
TYR
CZ
32.740
54.435
34.866
16.69


2501
TYR
OH
32.240
54.871
36.111
18.92


2502
TYR
H
31.850
53.689
29.886
20.00


2503
TYR
HA
33.628
51.368
29.650
20.00


2504
TYR
1HB
35.016
53.026
30.901
20.00


2505
TYR
2HB
34.748
51.510
31.713
20.00


2506
TYR
HD1
33.656
51.367
33.806
20.00


2507
TYR
HD2
33.632
55.018
31.619
20.00


2508
TYR
HE1
32.854
52.539
35.807
20.00


2509
TYR
HE2
32.615
56.155
33.358
20.00


2510
TYR
HH
31.864
55.766
36.179
20.00


2511
THR
N
32.096
50.092
31.166
14.21


2512
THR
CA
31.125
49.193
31.834
15.42


2513
THR
C
31.889
48.540
33.043
15.44


2514
THR
O
33.128
48.344
32.955
15.14


2515
THR
CB
30.572
48.077
30.896
16.15


2516
THR
OG1
29.894
48.442
29.632
16.75


2517
THR
CG2
29.525
47.168
31.562
15.21


2518
THR
H
33.038
49.794
31.028
20.00


2519
THR
HA
30.320
49.806
32.254
20.00


2520
THR
HB
31.408
47.328
30.806
20.00


2521
THR
HG1
30.097
49.274
29.118
20.00


2522
THR
1HG2
28.699
47.761
31.955
20.00


2523
THR
2HG2
29.934
46.590
32.391
20.00


2524
THR
3HG2
29.096
46.451
30.861
20.00


2525
VAL
N
31.079
48.256
34.137
14.25


2526
VAL
CA
31.584
47.499
35.318
15.61


2527
VAL
C
30.715
46.291
35.625
15.76


2528
VAL
O
29.577
46.421
36.050
16.87


2529
VAL
CB
31.794
48.216
36.666
15.56


2530
VAL
CG1
32.554
49.567
36.570
17.93


2531
VAL
CG2
32.587
47.191
37.535
15.84


2532
VAL
H
30.179
48.701
34.161
20.00


2533
VAL
HA
32.559
47.126
35.001
20.00


2534
VAL
HB
30.835
48.422
37.142
20.00


2535
VAL
1HG1
31.976
50.307
36.013
20.00


2536
VAL
2HG1
33.491
49.416
36.039
20.00


2537
VAL
3HG1
32.779
49.960
37.562
20.00


2538
VAL
1HG2
33.506
46.870
37.041
20.00


2539
VAL
2HG2
32.017
46.297
37.790
20.00


2540
VAL
3HG2
32.878
47.622
38.492
20.00


2541
ARG
N
31.313
45.111
35.451
15.23


2542
ARG
CA
30.636
43.909
35.796
12.90


2543
ARG
C
31.149
43.269
37.138
14.57


2544
ARG
O
32.271
43.418
37.622
14.51


2545
ARG
CB
30.918
42.912
34.683
12.22


2546
ARG
CG
30.854
43.522
33.366
14.22


2547
ARG
CD
30.693
42.427
32.294
17.43


2548
ARG
NE
30.223
43.114
31.092
19.70


2549
ARG
CZ
30.925
43.891
30.263
18.02


2550
ARG
NH1
32.183
44.065
30.512
20.75


2551
ARG
NH2
30.350
44.466
29.248
22.30


2552
ARG
H
32.298
45.147
35.294
20.00


2553
ARG
HA
29.568
44.091
35.867
20.00


2554
ARG
1HB
30.145
42.142
34.759
20.00


2555
ARG
2HB
31.835
42.363
34.817
20.00


2556
ARG
1HG
31.731
44.132
33.167
20.00


2557
ARG
2HG
29.999
44.186
33.307
20.00


2558
ARG
1HD
29.921
41.721
32.566
20.00


2559
ARG
2HD
31.619
41.882
32.095
20.00


2560
ARG
HE
29.220
43.100
30.923
20.00


2561
ARG
1HH1
32.774
44.675
29.993
20.00


2562
ARG
2HH1
32.503
43.503
31.261
20.00


2563
ARG
1HH2
30.802
45.007
28.545
20.00


2564
ARG
2HH2
29.341
44.378
29.241
20.00


2565
GLN
N
30.217
42.477
37.624
15.95


2566
GLN
CA
30.475
41.509
38.662
15.20


2567
GLN
C
30.211
40.123
38.070
14.98


2568
GLN
O
29.185
39.776
37.459
15.16


2569
GLN
CB
29.451
41.789
39.755
19.99


2570
GLN
OG
29.683
40.991
41.063
24.39


2571
GLN
CD
28.589
41.388
42.123
33.29


2572
GLN
OE1
27.850
42.381
41.972
36.18


2573
GLN
NE2
28.425
40.476
43.095
32.20


2574
GLN
H
29.312
42.543
37.204
20.00


2575
GLN
HA
31.495
41.611
39.033
20.00


2576
GLN
1HB
28.462
41.527
39.400
20.00


2577
GLN
2HB
29.459
42.847
40.009
20.00


2578
GLN
1HG
30.642
41.250
41.495
20.00


2579
GLN
2HG
29.662
39.915
40.893
20.00


2580
GLN
1HE2
27.641
40.580
43.693
20.00


2581
GLN
2HE2
29.140
39.806
43.302
20.00


2582
LEU
N
31.219
39.366
38.295
14.40


2583
LEU
CA
31.301
38.012
37.806
16.50


2584
LEU
C
31.384
37.122
39.071
17.55


2585
LEU
O
31.940
37.484
40.119
18.19


2586
LEU
CB
32.603
37.945
36.952
16.87


2587
LEU
CG
32.569
38.220
35.452
19.16


2588
LEU
CD1
33.846
38.919
35.104
18.62


2589
LEU
CD2
31.412
39.019
34.876
19.45


2590
LEU
H
31.971
39.750
38.837
20.00


2591
LEU
HA
30.417
37.737
37.232
20.00


2592
LEU
1HB
32.962
36.918
37.027
20.00


2593
LEU
2HB
33.381
38.510
37.469
20.00


2594
LEU
HG
32.559
37.262
34.932
20.00


2595
LEU
1HD1
34.685
38.249
35.290
20.00


2596
LEU
2HD1
33.982
39.781
35.756
20.00


2597
LEU
3HD1
33.894
39.241
34.066
20.00


2598
LEU
1HD2
31.346
40.006
35.343
20.00


2599
LEU
2HD2
30.471
38.515
35.066
20.00


2600
LEU
3HD2
31.492
39.169
33.798
20.00


2601
GLU
N
30.823
35.909
38.869
16.26


2602
GLU
CA
31.238
34.878
39.789
16.63


2603
GLU
C
32.084
33.768
39.058
15.84


2604
GLU
O
31.620
33.130
38.137
17.35


2605
GLU
CB
30.001
34.344
40.415
17.38


2606
GLU
CG
30.495
33.228
41.347
23.65


2607
GLU
CD
29.265
32.786
42.113
30.56


2608
GLU
OE1
28.878
33.608
42.914
31.25


2609
GLU
OE2
28.700
31.723
41.893
32.96


2610
GLU
H
30.319
35.716
38.030
20.00


2611
GLU
HA
31.850
35.274
40.600
20.00


2612
GLU
1HB
29.288
33.951
39.680
20.00


2613
GLU
2HB
29.485
35.129
40.974
20.00


2614
GLU
1HG
31.213
33.593
42.076
20.00


2615
GLU
2HG
30.933
32.393
40.798
20.00


2616
LEU
N
33.326
33.595
39.566
17.81


2617
LEU
CA
34.140
32.449
39.349
19.00


2618
LEU
C
33.940
31.282
40.390
21.54


2619
LEU
O
34.276
31.393
41.532
19.81


2620
LEU
CD
35.606
32.971
39.327
17.55


2621
LEU
CG
36.442
32.660
38.027
19.65


2622
LEU
CD1
36.241
31.301
37.304
20.83


2623
LEU
CD2
37.930
32.956
38.354
17.35


2624
LEU
H
33.557
34.257
40.273
20.00


2625
LEU
HA
33.888
32.074
38.357
20.00


2626
LEU
1HB
36.140
32.604
40.202
20.00


2627
LEU
2HB
35.640
34.051
39.468
20.00


2628
LEU
HG
36.150
33.394
37.288
20.00


2629
LEU
1HD1
35.238
31.140
36.918
20.00


2630
LEU
2HD1
36.429
30.499
38.028
20.00


2631
LEU
3HD1
36.940
31.166
36.483
20.00


2632
LEU
1HD2
38.241
32.718
39.355
20.00


2633
LEU
2HD2
38.125
34.026
38.251
20.00


2634
LEU
3HD2
38.604
32.454
37.658
20.00


2635
GLU
N
33.496
30.126
39.911
24.40


2636
GLU
CA
33.575
28.858
40.619
24.80


2637
GLU
C
34.665
27.956
40.054
25.64


2638
GLU
O
34.768
27.641
38.858
24.49


2639
GLU
CB
32.249
28.090
40.382
24.55


2640
GLU
CG
31.925
27.011
41.455
26.49


2641
GLU
CD
30.506
26.410
41.400
28.97


2642
GLU
OE1
29.575
26.949
40.725
33.55


2643
GLU
OE2
30.384
25.331
42.024
32.02


2644
GLU
H
33.173
30.112
38.963
20.00


2645
GLU
HA
33.711
29.057
41.677
20.00


2646
GLU
1HB
32.211
27.646
39.397
20.00


2647
GLU
2HB
31.442
28.819
40.405
20.00


2648
GLU
1HG
32.032
27.435
42.451
20.00


2649
GLU
2HG
32.627
26.180
41.374
20.00


2650
ASN
N
35.429
27.522
41.022
26.33


2651
ASN
CA
36.257
26.375
40.918
28.36


2652
ASN
C
35.484
25.105
41.356
29.60


2653
ASN
O
35.519
24.635
42.483
31.34


2654
ASN
CB
37.592
26.666
41.584
27.93


2655
ASN
CG
38.437
25.448
41.952
30.21


2656
ASN
OD1
38.104
24.312
41.659
28.62


2657
ASN
ND2
39.585
25.727
42.536
31.76


2658
ASN
H
35.202
27.900
41.924
20.00


2659
ASN
HA
36.506
26.230
39.865
20.00


2660
ASN
1HB
37.424
27.336
42.384
20.00


2661
ASN
2HB
38.200
27.247
40.895
20.00


2662
ASN
1HD2
40.189
24.947
42.678
20.00


2663
ASN
2HD2
39.765
26.675
42.775
20.00


2664
LEU
N
34.921
24.563
40.253
30.56


2665
LEU
CA
34.285
23.303
40.064
31.30


2666
LEU
C
35.081
22.185
40.712
35.28


2667
LEU
O
34.408
21.328
41.256
35.62


2668
LEU
CB
34.110
23.167
38.540
28.95


2669
LEU
CG
32.712
23.388
37.955
29.38


2670
LEU
CD1
32.843
23.432
36.457
27.85


2671
LEU
CD2
32.026
24.649
38.417
30.00


2672
LEU
H
35.069
25.106
39.427
20.00


2673
LEU
HA
33.325
23.325
40.583
20.00


2674
LEU
1HB
34.448
22.177
38.227
20.00


2675
LEU
2HB
34.784
23.849
38.045
20.00


2676
LEU
HG
32.087
22.541
38.236
20.00


2677
LEU
1HD1
33.274
22.495
36.092
20.00


2678
LEU
2HD1
33.477
24.257
36.130
20.00


2679
LEU
3HD1
31.871
23.548
35.979
20.00


2680
LEU
1HD2
32.635
25.524
38.200
20.00


2681
LEU
2HD2
31.877
24.617
39.498
20.00


2682
LEU
3HD2
31.046
24.777
37.961
20.00


2683
THR
N
36.468
22.190
40.736
37.71


2684
THR
CA
37.202
21.155
41.533
41.16


2685
THR
C
36.825
21.148
43.051
43.17


2686
THR
O
36.644
20.102
43.667
45.18


2687
THR
CB
38.736
21.197
41.432
44.16


2688
THR
OG1
39.177
21.273
40.028
45.45


2689
THR
CG2
39.401
20.134
42.369
44.74


2690
THR
H
36.994
22.868
40.211
20.00


2691
THR
HA
36.832
20.195
41.169
20.00


2692
THR
HB
38.994
22.162
41.936
20.00


2693
THR
HG1
39.493
20.516
39.481
20.00


2694
THR
1HG2
39.074
19.099
42.217
20.00


2695
THR
2HG2
39.155
20.320
43.413
20.00


2696
THR
3HG2
40.498
20.158
42.403
20.00


2697
THR
N
36.755
22.357
43.620
43.51


2698
THR
CA
36.569
22.492
45.080
40.76


2699
THR
C
35.225
23.028
45.501
41.34


2700
THR
O
34.949
23.173
46.685
43.02


2701
THR
CB
37.422
23.692
45.561
39.25


2702
THR
OG1
37.152
25.022
44.987
42.09


2703
THR
CG2
38.908
23.417
45.377
37.92


2704
THR
H
36.887
23.135
43.004
20.00


2705
THR
HA
36.765
21.561
45.612
20.00


2706
THR
HB
37.364
23.699
46.689
20.00


2707
THR
HG1
36.526
25.122
44.220
20.00


2708
THR
1HG2
39.205
23.284
44.335
20.00


2709
THR
2HG2
39.175
22.506
45.911
20.00


2710
THR
3HG2
39.483
24.240
45.802
20.00


2711
GLN
N
34.476
23.431
44.476
40.94


2712
GLN
CA
33.352
24.345
44.557
41.20


2713
GLN
C
33.545
25.695
45.299
38.70


2714
GLN
O
32.586
26.414
45.546
38.13


2715
GLN
CB
32.149
23.549
45.037
45.37


2716
GLN
CG
31.786
22.523
43.980
51.51


2717
GLN
CD
30.414
21.959
44.267
56.44


2718
GLN
OE1
30.270
21.226
45.234
58.04


2719
GLN
NE2
29.438
22.272
43.407
61.09


2720
GLN
H
34.741
23.135
43.558
20.00


2721
GLN
HA
33.160
24.656
43.530
20.00


2722
GLN
1HB
31.310
24.234
45.188
20.00


2723
GLN
2HB
32.358
23.063
45.989
20.00


2724
GLN
1HG
32.495
21.702
43.926
20.00


2725
GLN
2HG
31.753
22.994
42.994
20.00


2726
GLN
1HE2
28.585
21.754
43.419
20.00


2727
GLN
2HE2
29.601
22.971
42.703
20.00


2728
GLU
N
34.762
26.092
45.656
37.29


2729
GLU
CA
34.911
27.514
46.023
37.74


2730
GLU
C
34.377
28.454
44.928
35.73


2731
GLU
O
34.427
28.209
43.728
34.94


2732
GLU
CB
36.317
27.954
46.489
43.18


2733
GLU
CG
36.377
29.427
47.019
51.01


2734
GLU
CD
37.799
29.866
47.427
57.11


2735
GLU
OE1
38.637
29.023
47.594
59.70


2736
GLU
OE2
38.063
31.062
47.546
59.23


2737
GLU
H
35.487
25.418
45.773
20.00


2738
GLU
HA
34.261
27.618
46.889
20.00


2739
GLU
1HB
37.020
27.876
45.674
20.00


2740
GLU
2HB
36.685
27.267
47.255
20.00


2741
GLU
1HG
35.747
29.531
47.902
20.00


2742
GLU
2HG
36.060
30.154
46.279
20.00


2743
THR
N
33.861
29.566
45.444
33.44


2744
THR
CA
33.250
30.618
44.592
31.67


2745
THR
C
33.937
31.934
44.874
30.34


2746
THR
O
34.285
32.227
46.011
31.62


2747
THR
CB
31.701
30.674
44.951
29.52


2748
THR
OG1
31.012
29.973
43.882
31.41


2749
THR
CG2
31.094
31.901
45.741
27.83


2750
THR
H
34.048
29.665
46.415
20.00


2751
THR
HA
33.482
30.372
43.553
20.00


2752
THR
HB
31.695
30.004
45.845
20.00


2753
THR
HG1
30.437
30.433
43.203
20.00


2754
THR
1HG2
31.122
32.846
45.187
20.00


2755
THR
2HG2
31.678
32.101
46.635
20.00


2756
THR
3HG2
30.068
31.750
46.091
20.00


2757
ARG
N
34.107
32.738
43.860
27.40


2758
ARG
CA
34.538
34.090
44.139
22.96


2759
ARG
C
33.959
35.067
43.175
19.60


2760
ARG
O
33.722
34.760
42.031
18.08


2761
ARG
CB
36.078
34.229
44.003
24.02


2762
ARG
CG
36.854
33.227
44.797
27.06


2763
ARG
CD
38.285
33.547
44.508
30.34


2764
ARG
NE
39.183
32.683
45.219
31.08


2765
ARG
CZ
40.370
32.287
44.813
33.27


2766
ARG
NH1
41.054
32.842
43.773
28.01


2767
ARG
NH2
40.742
31.202
45.477
34.77


2768
ARG
H
33.782
32.444
42.964
20.00


2769
ARG
HA
34.184
34.369
45.135
20.00


2770
ARG
1HB
36.387
35.247
44.261
20.00


2771
ARG
2HB
36.342
34.082
42.952
20.00


2772
ARG
1HG
36.606
32.197
44.535
20.00


2773
ARG
2HG
36.637
33.357
45.857
20.00


2774
ARG
1HD
38.521
34.562
44.846
20.00


2775
ARG
2HD
38.485
33.476
43.435
20.00


2776
ARG
HE
38.854
32.134
45.993
20.00


2777
ARG
1HH1
41.905
32.439
43.426
20.00


2778
ARG
2HH1
40.666
33.647
43.339
20.00


2779
ARG
1HH2
41.602
30.761
45.232
20.00


2780
ARG
2HH2
40.159
30.814
46.201
20.00


2781
GLU
N
33.859
36.255
43.731
19.61


2782
GLU
CA
33.468
37.442
43.053
20.49


2783
GLU
C
34.699
38.231
42.582
18.35


2784
GLU
O
35.609
38.648
43.324
19.50


2785
GLU
CB
32.651
38.383
43.905
23.73


2786
GLU
CG
32.354
39.674
43.116
30.58


2787
GLU
CD
31.697
40.680
44.039
37.37


2788
GLU
OE1
32.349
41.643
44.394
42.91


2789
GLU
OE2
30.572
40.459
44.434
39.95


2790
GLU
H
34.048
36.277
44.708
20.00


2791
GLU
HA
32.845
37.134
42.209
20.00


2792
GLU
1HB
33.179
38.620
44.825
20.00


2793
GLU
2HB
31.718
37.904
44.224
20.00


2794
GLU
1HG
31.671
39.438
42.299
20.00


2795
GLU
2HG
33.211
40.145
42.652
20.00


2796
ILE
N
34.562
38.431
41.227
17.31


2797
ILE
CA
35.533
39.098
40.423
15.44


2798
ILE
C
34.806
40.329
39.820
13.03


2799
ILE
O
33.725
40.269
39.307
13.73


2800
ILE
CB
36.014
38.081
39.316
14.77


2801
ILE
CG1
36.469
36.717
39.808
13.99


2802
ILE
CG2
37.156
38.781
38.511
13.81


2803
ILE
CD1
37.777
36.731
40.616
13.39


2804
ILE
H
33.698
38.103
40.833
20.00


2805
ILE
HA
36.373
39.393
41.053
20.00


2806
ILE
HB
35.178
37.891
38.645
20.00


2807
ILE
1HG1
36.634
36.068
38.940
20.00


2808
ILE
2HG1
35.686
36.219
40.382
20.00


2809
ILE
1HG2
37.976
39.123
39.142
20.00


2810
ILE
2HG2
36.753
39.664
38.013
20.00


2811
ILE
3HG2
37.571
38.142
37.731
20.00


2812
ILE
1HD1
37.651
37.273
41.553
20.00


2813
ILE
2HD1
38.583
37.221
40.068
20.00


2814
ILE
3HD1
38.126
35.731
40.878
20.00


2815
LEU
N
35.437
41.444
39.855
9.92


2816
LEU
CA
34.934
42.684
39.281
10.85


2817
LEU
C
35.639
42.986
37.908
12.45


2818
LEU
O
36.823
42.846
37.768
13.72


2819
LEU
CB
35.395
43.657
40.382
11.52


2820
LEU
CG
34.233
43.955
41.312
17.76


2821
LEU
CD1
34.708
44.759
42.493
14.86


2822
LEU
CD2
33.503
42.721
41.757
15.60


2823
LEU
H
36.344
41.402
40.277
20.00


2824
LEU
HA
33.859
42.644
39.125
20.00


2825
LEU
1HB
35.739
44.594
39.965
20.00


2826
LEU
2HB
36.256
43.272
40.931
20.00


2827
LEU
HG
33.518
44.568
40.763
20.00


2828
LEU
1HD1
35.021
45.750
42.182
20.00


2829
LEU
2HD1
35.528
44.252
42.999
20.00


2830
LEU
3HD1
33.915
44.895
43.226
20.00


2831
LEU
1HD2
34.144
41.977
42.215
20.00


2832
LEU
2HD2
32.928
42.261
40.949
20.00


2833
LEU
3HD2
32.747
43.012
42.487
20.00


2834
HIS
N
34.933
43.394
36.894
10.68


2835
HIS
CA
35.545
43.475
35.600
11.55


2836
HIS
C
35.323
44.872
35.144
12.79


2837
HIS
O
34.194
45.266
34.919
14.70


2838
HIS
CB
34.788
42.489
34.668
11.04


2839
HIS
CG
35.263
42.384
33.227
9.68


2840
HIS
ND1
34.526
42.828
32.187
10.25


2841
HIS
CD2
36.429
41.786
32.744
10.64


2842
HIS
CE1
35.183
42.511
31.063
12.62


2843
HIS
NE2
36.329
41.906
31.409
11.21


2844
HIS
H
33.982
43.625
37.069
20.00


2845
HIS
HA
36.601
43.242
35.581
20.00


2846
HIS
1HB
33.743
42.742
34.647
20.00


2847
HIS
2HB
34.856
41.492
35.083
20.00


2848
HIS
HD1
33.677
43.272
32.321
20.00


2849
HIS
HD2
37.206
41.325
33.337
20.00


2850
HIS
HE1
34.876
42.676
30.032
20.00


2851
PHE
N
36.438
45.608
34.939
12.23


2852
PHE
CA
36.352
47.028
34.537
10.89


2853
PHE
C
36.685
47.113
33.028
13.34


2854
PHE
O
37.811
46.965
32.583
13.55


2855
PHE
CB
37.334
47.858
35.441
10.80


2856
PHE
CG
37.058
47.717
36.947
11.64


2857
PHE
CD1
37.655
46.741
37.702
11.60


2858
PHE
CD2
36.134
48.520
37.567
14.48


2859
PHE
CE1
37.264
46.493
39.006
12.91


2860
PHE
CE2
35.739
48.287
38.862
15.96


2861
PHE
CZ
36.291
47.267
39.581
13.40


2862
PHE
H
37.310
45.176
35.152
20.00


2863
PHE
HA
35.335
47.384
34.690
20.00


2864
PHE
1HB
37.275
48.922
35.204
20.00


2865
PHE
2HB
38.366
47.564
35.244
20.00


2866
PHE
HD1
38.413
46.112
37.256
20.00


2867
PHE
HD2
35.694
49.334
37.003
20.00


2868
PHE
HE1
37.715
45.660
39.525
20.00


2869
PHE
HE2
34.999
48.915
39.328
20.00


2870
PHE
HZ
35.930
47.074
40.572
20.00


2871
HIS
N
35.639
47.337
32.230
11.63


2872
HIS
CA
35.829
47.375
30.802
10.69


2873
HIS
C
35.809
48.820
30.319
11.28


2874
HIS
O
34.778
49.477
30.311
10.79


2875
HIS
CB
34.731
46.513
30.278
11.78


2876
HIS
CG
34.919
46.186
28.833
10.24


2877
HIS
ND1
35.782
46.799
27.957
13.45


2878
HIS
CD2
34.178
45.239
28.132
9.09


2879
HIS
CE1
35.554
46.232
26.766
8.49


2880
HIS
NE2
34.587
45.287
26.854
12.97


2881
HIS
H
34.770
47.509
32.693
20.00


2882
HIS
HA
36.801
46.952
30.534
20.00


2883
HIS
1HB
33.769
46.998
30.395
20.00


2884
HIS
2HB
34.712
45.579
30.833
20.00


2885
HIS
HD1
36.458
47.499
28.105
20.00


2886
HIS
HD2
33.424
44.566
28.470
20.00


2887
HIS
HE1
35.972
46.552
25.831
20.00


2888
TYR
N
36.961
49.274
29.879
10.13


2889
TYR
CA
37.059
50.545
29.109
11.53


2890
TYR
C
36.769
50.315
27.571
12.75


2891
TYR
O
37.466
49.547
26.883
11.94


2892
TYR
CB
38.465
51.130
29.407
12.91


2893
TYR
CG
38.500
52.618
29.205
14.41


2894
TYR
CD1
38.303
53.125
27.967
12.62


2895
TYR
CD2
38.816
53.503
30.229
14.67


2896
TYR
CE1
38.422
54.506
27.769
14.22


2897
TYR
CE2
38.884
54.882
30.077
15.77


2898
TYR
CZ
38.608
55.421
28.834
16.57


2899
TYR
OH
38.583
56.821
28.797
18.08


2900
TYR
H
37.739
48.639
29.964
20.00


2901
TYR
HA
36.319
51.229
29.522
20.00


2902
TYR
1HB
39.183
50.677
28.729
20.00


2903
TYR
2HB
38.782
50.884
30.426
20.00


2904
TYR
HD1
38.125
52.492
27.111
20.00


2905
TYR
HD2
39.029
53.064
31.176
20.00


2906
TYR
HE1
38.636
54.616
26.713
20.00


2907
TYR
HE2
39.100
55.550
30.901
20.00


2908
TYR
HH
38.117
57.229
28.064
20.00


2909
THR
N
35.664
50.941
27.075
13.66


2910
THR
CA
35.217
50.519
25.758
14.87


2911
THR
C
35.474
51.605
24.708
16.37


2912
THR
O
35.293
51.365
23.530
19.74


2913
THR
CB
33.766
50.067
25.763
13.92


2914
THR
OG1
32.985
51.270
25.886
14.21


2915
THR
CG2
33.452
48.853
26.638
14.13


2916
THR
H
35.138
51.598
27.614
20.00


2917
THR
HA
35.810
49.689
25.389
20.00


2918
THR
HB
33.665
49.671
24.715
20.00


2919
THR
HG1
32.608
51.609
26.739
20.00


2920
THR
1HG2
33.804
48.858
27.675
20.00


2921
THR
2HG2
33.975
48.036
26.159
20.00


2922
THR
3HG2
32.412
48.517
26.599
20.00


2923
THR
N
35.980
52.791
25.104
17.79


2924
THR
CA
36.277
53.829
24.097
17.71


2925
THR
C
37.780
54.268
23.978
17.22


2926
THR
O
38.171
55.337
23.501
19.49


2927
THR
CB
35.414
55.056
24.407
20.00


2928
THR
OG1
35.794
55.465
25.757
22.57


2929
THR
CG2
33.969
54.696
24.541
17.86


2930
THR
H
35.848
53.085
26.052
20.00


2931
THR
HA
35.998
53.464
23.110
20.00


2932
THR
HB
35.386
55.656
23.415
20.00


2933
THR
HG1
36.368
56.268
25.953
20.00


2934
THR
1HG2
33.838
53.994
25.327
20.00


2935
THR
2HG2
33.561
54.280
23.626
20.00


2936
THR
3HG2
33.378
55.567
24.814
20.00


2937
TRP
N
38.641
53.346
24.336
13.24


2938
TRP
CA
40.120
53.598
24.218
11.42


2939
TRP
C
40.640
52.873
22.987
11.23


2940
TRP
O
40.679
51.639
22.980
13.88


2941
TRP
CB
40.854
53.065
25.467
10.59


2942
TRP
CG
42.300
53.478
25.605
10.86


2943
TRP
CD1
43.194
53.926
24.620
10.44


2944
TRP
CD2
43.010
53.434
26.877
11.23


2945
TRP
NE1
44.399
54.166
25.165
11.38


2946
TRP
CE2
44.332
53.890
26.576
11.59


2947
TRP
CE3
42.647
53.113
28.170
12.73


2948
TRP
CZ2
45.251
54.034
27.615
9.06


2949
TRP
CZ3
43.596
53.268
29.207
11.86


2950
TRP
CH2
44.901
53.730
28.923
9.08


2951
TRP
H
38.223
52.591
24.823
20.00


2952
TRP
HA
40.290
54.667
24.218
20.00


2953
TRP
1HB
40.803
51.977
25.516
20.00


2954
TRP
2HB
40.369
53.437
26.358
20.00


2955
TRP
HD1
42.974
54.062
23.567
20.00


2956
TRP
HE1
45.198
54.476
24.680
20.00


2957
TRP
HE3
41.644
52.763
28.381
20.00


2958
TRP
HZ2
46.233
54.366
27.330
20.00


2959
TRP
HZ3
43.327
53.028
30.234
20.00


2960
TRP
HH2
45.624
53.867
29.709
20.00


2961
PRO
N
41.054
53.592
21.917
11.63


2962
PRO
CA
41.341
52.864
20.657
12.03


2963
PRO
C
42.762
52.223
20.620
10.91


2964
PRO
O
43.674
52.589
21.352
11.74


2965
PRO
CB
41.002
53.928
19.599
15.45


2966
PRO
CG
40.318
55.060
20.382
16.92


2967
PRO
CD
40.930
55.068
21.726
12.40


2968
PRO
HA
40.641
52.036
20.543
20.00


2969
PRO
1HB
40.376
53.540
18.790
20.00


2970
PRO
2HB
41.911
54.325
19.146
20.00


2971
PRO
1HG
40.429
56.033
19.909
20.00


2972
PRO
2HG
39.258
54.863
20.489
20.00


2973
PRO
1HD
40.296
55.584
22.434
20.00


2974
PRO
2HD
41.916
55.543
21.732
20.00


2975
ASP
N
42.866
51.223
19.711
9.83


2976
ASP
CA
44.171
50.530
19.648
13.50


2977
ASP
C
45.160
51.471
19.077
15.42


2978
ASP
O
44.802
52.201
18.172
16.15


2979
ASP
CB
44.065
49.223
18.819
14.19


2980
ASP
CG
45.153
48.241
19.221
17.10


2981
ASP
OD1
45.877
48.540
20.150
16.38


2982
ASP
OD2
45.270
47.155
18.676
16.84


2983
ASP
H
42.077
50.813
19.277
20.00


2984
ASP
HA
44.449
50.328
20.691
20.00


2985
ASP
1HB
44.135
49.419
17.751
20.00


2986
ASP
2HB
43.120
48.725
19.033
20.00


2987
PHE
N
46.329
51.527
19.651
15.66


2988
PHE
CA
47.349
52.538
19.450
13.22


2989
PHE
C
46.921
54.020
19.555
13.65


2990
PHE
O
47.504
54.923
18.956
14.13


2991
PHE
CB
48.233
52.272
18.290
15.03


2992
PHE
CG
48.749
50.895
18.233
16.37


2993
PHE
CD1
49.950
50.591
18.833
12.85


2994
PHE
CD2
48.009
49.927
17.529
15.04


2995
PHE
CE1
50.376
49.294
18.803
10.54


2996
PHE
CE2
48.460
48.659
17.407
12.82


2997
PHE
CZ
49.626
48.341
18.105
12.68


2998
PHE
H
46.546
50.666
20.113
20.00


2999
PHE
HA
47.975
52.405
20.321
20.00


3000
PHE
1HB
49.022
53.011
18.302
20.00


3001
PHE
2HB
47.662
52.452
17.380
20.00


3002
PHE
HD1
50.490
51.363
19.335
20.00


3003
PHE
HD2
47.070
50.181
17.066
20.00


3004
PHE
HE1
51.281
48.969
19.299
20.00


3005
PHE
HE2
47.901
47.906
16.873
20.00


3006
PHE
HZ
49.963
47.312
18.117
20.00


3007
GLY
N
45.887
54.153
20.424
12.17


3008
GLY
CA
45.240
55.436
20.680
12.74


3009
GLY
C
45.436
55.859
22.144
13.53


3010
GLY
O
46.132
55.250
22.953
12.80


3011
GLY
H
45.489
53.315
20.797
20.00


3012
GLY
1HA
44.176
55.267
20.536
20.00


3013
GLY
2HA
45.596
56.211
19.988
20.00


3014
VAL
N
44.801
56.938
22.435
14.29


3015
VAL
CA
44.812
57.503
23.722
13.36


3016
VAL
C
43.249
57.513
24.071
15.85


3017
VAL
O
42.426
57.380
23.136
16.84


3018
VAL
CB
45.673
58.788
23.744
12.64


3019
VAL
CG1
45.201
59.840
22.763
13.96


3020
VAL
CG2
47.178
58.444
23.585
12.56


3021
VAL
H
44.211
57.343
21.732
20.00


3022
VAL
HA
45.291
56.801
24.402
20.00


3023
VAL
HB
45.561
59.232
24.737
20.00


3024
VAL
1HG1
44.171
60.133
22.945
20.00


3025
VAL
2HG1
45.278
59.537
21.722
20.00


3026
VAL
3HG1
45.807
60.743
22.867
20.00


3027
VAL
1HG2
47.395
58.056
22.589
20.00


3028
VAL
2HG2
47.478
57.697
24.315
20.00


3029
VAL
3HG2
47.782
59.337
23.714
20.00


3030
PRO
N
42.963
57.517
25.476
16.09


3031
PRO
CA
41.668
57.936
26.088
14.29


3032
PRO
C
41.138
59.345
25.657
16.70


3033
PRO
O
41.887
60.270
25.348
15.47


3034
PRO
CB
42.035
58.106
27.586
12.24


3035
PRO
CG
43.260
57.208
27.767
11.83


3036
PRO
CD
44.019
57.339
26.463
14.99


3037
PRO
HA
40.885
57.194
25.936
20.00


3038
PRO
1HB
41.236
57.797
28.246
20.00


3039
PRO
2HB
42.288
59.134
27.841
20.00


3040
PRO
1HG
43.844
57.437
28.646
20.00


3041
PRO
2HG
42.915
56.182
27.868
20.00


3042
PRO
1HD
44.640
56.472
26.300
20.00


3043
PRO
2HD
44.642
58.226
26.489
20.00


3044
GLU
N
39.830
59.499
25.747
18.37


3045
GLU
CA
39.149
60.735
25.401
20.99


3046
GLU
C
39.701
61.877
26.121
22.01


3047
GLU
O
39.946
62.949
25.567
24.26


3048
GLU
CB
37.652
60.699
25.572
22.54


3049
GLU
CG
37.095
59.481
24.814
31.50


3050
GLU
CD
36.818
58.252
25.737
36.66


3051
GLU
OE1
37.792
57.706
26.363
31.28


3052
GLU
OE2
35.603
57.899
25.789
36.17


3053
GLU
H
39.307
58.672
25.934
20.00


3054
GLU
HA
39.384
60.894
24.354
20.00


3055
GLU
1HB
37.225
61.596
25.130
20.00


3056
GLU
2HB
37.322
60.660
26.604
20.00


3057
GLU
1HG
37.751
59.146
24.012
20.00


3058
GLU
2HG
36.147
59.734
24.345
20.00


3059
SER
N
39.960
61.603
27.399
20.38


3060
SER
CA
40.647
62.714
28.080
17.88


3061
SER
C
41.167
62.167
29.306
15.08


3062
SER
O
40.789
61.054
29.671
14.67


3063
SER
CB
39.666
63.853
28.431
16.14


3064
SER
OG
38.604
63.400
29.339
13.25


3065
SER
H
39.673
60.707
27.729
20.00


3066
SER
HA
41.461
63.055
27.454
20.00


3067
SER
1HB
39.386
64.462
27.511
20.00


3068
SER
2HB
40.217
64.669
28.926
20.00


3069
SER
HG
38.043
62.566
29.237
20.00


3070
PRO
N
42.046
62.978
29.961
17.02


3071
PRO
CA
42.562
62.555
31.277
16.44


3072
PRO
C
41.527
62.381
32.332
16.53


3073
PRO
O
41.596
61.476
33.162
15.74


3074
PRO
CB
43.653
63.578
31.636
16.53


3075
PRO
CG
43.993
64.277
30.294
18.72


3076
PRO
CD
42.716
64.193
29.431
16.72


3077
PRO
HA
43.044
61.584
31.179
20.00


3078
PRO
1HB
44.530
63.132
32.109
20.00


3079
PRO
2HB
43.256
64.327
32.324
20.00


3080
PRO
1HG
44.374
65.291
30.432
20.00


3081
PRO
2HG
44.794
63.718
29.803
20.00


3082
PRO
1HD
42.963
64.147
28.370
20.00


3083
PRO
2HD
42.115
65.075
29.631
20.00


3084
ALA
N
40.466
63.193
32.219
16.66


3085
ALA
CA
39.366
63.113
33.208
16.12


3086
ALA
C
38.576
61.824
33.103
15.23


3087
ALA
O
38.319
61.127
34.062
15.53


3088
ALA
CB
38.449
64.319
32.990
15.29


3089
ALA
H
40.478
63.899
31.513
20.00


3090
ALA
HA
39.809
63.153
34.207
20.00


3091
ALA
1HB
38.110
64.430
31.968
20.00


3092
ALA
2HB
38.976
65.236
33.241
20.00


3093
ALA
3HB
37.586
64.273
33.637
20.00


3094
SER
N
38.207
61.442
31.920
15.32


3095
SER
CA
37.563
60.086
31.870
15.79


3096
SER
C
38.482
58.892
32.167
13.45


3097
SER
O
38.104
57.921
32.825
13.08


3098
SER
CB
37.106
59.914
30.447
17.95


3099
SER
OG
38.030
60.657
29.618
26.88


3100
SER
H
38.374
62.009
31.111
20.00


3101
SER
HA
36.720
60.060
32.554
20.00


3102
SER
1HB
36.110
60.396
30.400
20.00


3103
SER
2HB
36.640
58.920
30.206
20.00


3104
SER
HG
38.996
60.405
29.428
20.00


3105
PHE
N
39.774
59.018
31.727
13.85


3106
PHE
CA
40.788
57.998
32.090
12.76


3107
PHE
C
40.881
57.892
33.605
12.10


3108
PHE
O
40.898
56.801
34.114
14.79


3109
PHE
CB
42.188
58.305
31.403
14.01


3110
PHE
CG
43.256
57.467
32.071
12.89


3111
PHE
CD1
43.459
56.157
31.644
10.70


3112
PHE
CD2
44.026
57.962
33.147
15.33


3113
PHE
CE1
44.455
55.390
32.240
13.65


3114
PHE
CE2
44.962
57.161
33.827
13.88


3115
PHE
CZ
45.203
55.884
33.321
14.38


3116
PHE
H
40.011
59.805
31.151
20.00


3117
PHE
HA
40.420
57.039
31.724
20.00


3118
PHE
1HB
42.428
59.353
31.538
20.00


3119
PHE
2HB
42.148
58.111
30.338
20.00


3120
PHE
HD1
42.865
55.751
30.834
20.00


3121
PHE
HD2
43.878
58.976
33.489
20.00


3122
PHE
HE1
44.653
54.393
31.863
20.00


3123
PHE
HE2
45.523
57.524
34.685
20.00


3124
PHE
HZ
45.964
55.260
33.765
20.00


3125
LEU
N
40.947
59.079
34.274
13.17


3126
LEU
CA
41.247
59.248
35.713
11.98


3127
LEU
C
40.029
58.870
36.513
11.69


3128
LEU
O
40.128
58.021
37.389
10.86


3129
LEU
CB
41.632
60.677
36.115
11.49


3130
LEU
CG
43.049
61.075
35.775
9.71


3131
LEU
CD1
44.161
60.504
36.812
12.65


3132
LEU
CD2
43.046
62.608
35.515
12.34


3133
LEU
H
40.884
59.875
33.675
20.00


3134
LEU
HA
42.051
58.546
35.951
20.00


3135
LEU
1HB
41.509
60.842
37.187
20.00


3136
LEU
2HB
40.927
61.358
35.635
20.00


3137
LEU
HG
43.285
60.627
34.817
20.00


3138
LEU
1HD1
44.121
59.416
36.874
20.00


3139
LEU
2HD1
43.969
60.871
37.820
20.00


3140
LEU
3HD1
45.175
60.780
36.532
20.00


3141
LEU
1HD2
42.831
63.130
36.448
20.00


3142
LEU
2HD2
42.314
62.959
34.794
20.00


3143
LEU
3HD2
44.031
62.930
35.184
20.00


3144
ASN
N
38.872
59.446
36.129
13.52


3145
ASN
CA
37.574
58.890
36.526
14.70


3146
ASN
C
37.456
57.332
36.437
13.68


3147
ASN
O
37.238
56.742
37.481
13.48


3148
ASN
CB
36.423
59.673
35.859
15.31


3149
ASN
CG
35.033
59.150
36.303
16.04


3150
ASN
OD1
34.813
59.091
37.511
17.67


3151
ASN
ND2
34.127
58.751
35.405
15.77


3152
ASN
H
38.965
60.202
35.486
20.00


3153
ASN
HA
37.544
59.107
37.591
20.00


3154
ASN
1HB
36.509
59.883
34.794
20.00


3155
ASN
2HB
36.434
60.658
36.318
20.00


3156
ASN
1HD2
33.321
58.374
35.886
20.00


3157
ASN
2HD2
34.246
58.811
34.418
20.00


3158
PHE
N
37.671
56.657
35.281
12.27


3159
PHE
CA
37.848
55.157
35.199
11.60


3160
PHE
C
38.826
54.528
36.216
11.61


3161
PHE
O
38.507
53.684
37.018
13.15


3162
PHE
CB
38.317
54.735
33.790
11.94


3163
PHE
CG
38.417
53.234
33.582
11.78


3164
PHE
CD1
39.644
52.558
33.626
14.00


3165
PHE
CD2
37.292
52.475
33.355
11.64


3166
PHE
CE1
39.718
51.158
33.535
10.61


3167
PHE
CE2
37.370
51.102
33.252
12.07


3168
PHE
CZ
38.565
50.426
33.352
10.24


3169
PHE
H
37.841
57.232
34.482
20.00


3170
PHE
HA
36.884
54.701
35.429
20.00


3171
PHE
1HB
39.285
55.186
33.567
20.00


3172
PHE
2HB
37.678
55.105
32.995
20.00


3173
PHE
HD1
40.553
53.144
33.746
20.00


3174
PHE
HD2
36.350
52.985
33.259
20.00


3175
PHE
HE1
40.676
50.645
33.599
20.00


3176
PHE
HE2
36.457
50.539
33.082
20.00


3177
PHE
HZ
38.602
49.351
33.281
20.00


3178
LEU
N
40.060
54.928
36.155
10.72


3179
LEU
CA
41.129
54.468
37.080
10.36


3180
LEU
C
40.671
54.520
38.579
11.41


3181
LEU
O
40.734
53.555
39.309
8.72


3182
LEU
CB
42.457
55.335
36.829
9.30


3183
LEU
CG
43.531
55.094
37.943
11.24


3184
LEU
CD1
44.819
55.890
37.855
9.97


3185
LEU
CD2
43.880
53.666
38.148
8.08


3186
LEU
H
40.230
55.612
35.446
20.00


3187
LEU
HA
41.306
53.427
36.811
20.00


3188
LEU
1HB
42.214
56.395
36.816
20.00


3189
LEU
2HB
42.881
55.113
35.846
20.00


3190
LEU
HG
43.084
55.415
38.883
20.00


3191
LEU
1HD1
44.605
56.957
37.902
20.00


3192
LEU
2HD1
45.361
55.713
36.926
20.00


3193
LEU
3HD1
45.489
55.647
38.679
20.00


3194
LEU
1HD2
44.339
53.255
37.248
20.00


3195
LEU
2HD2
43.033
53.027
38.390
20.00


3196
LEU
3HD2
44.625
53.549
38.936
20.00


3197
PHE
N
40.227
55.702
38.999
13.37


3198
PHE
CA
39.608
55.966
40.304
14.13


3199
PHE
C
38.419
55.074
40.584
14.10


3200
PHE
O
38.421
54.432
41.582
16.46


3201
PHE
CB
39.373
57.460
40.466
14.59


3202
PHE
CG
40.608
58.108
41.004
17.38


3203
PHE
CD1
41.729
58.330
40.223
17.66


3204
PHE
CD2
40.649
58.448
42.351
20.46


3205
PHE
CE1
42.902
58.849
40.752
17.85


3206
PHE
CE2
41.842
58.951
42.901
21.97


3207
PHE
CZ
42.980
59.145
42.099
19.00


3208
PHE
H
40.315
56.444
38.339
20.00


3209
PHE
HA
40.353
55.693
41.035
20.00


3210
PHE
1HB
38.539
57.656
41.135
20.00


3211
PHE
2HB
39.078
57.912
39.521
20.00


3212
PHE
HD1
41.687
58.093
39.172
20.00


3213
PHE
HD2
39.778
58.316
42.988
20.00


3214
PHE
HE1
43.761
58.990
40.117
20.00


3215
PHE
HE2
41.841
59.192
43.957
20.00


3216
PHE
HZ
43.888
59.517
42.548
20.00


3217
LYS
N
37.472
54.865
39.696
14.03


3218
LYS
CA
36.583
53.707
39.921
13.68


3219
LYS
C
37.382
52.381
40.226
13.76


3220
LYS
O
37.060
51.643
41.128
13.17


3221
LYS
CB
35.710
53.494
38.629
17.74


3222
LYS
CG
34.241
53.905
38.681
26.69


3223
LYS
CD
33.252
52.778
39.167
32.82


3224
LYS
CE
31.708
53.171
39.423
34.45


3225
LYS
NZ
30.586
52.149
39.327
39.18


3226
LYS
H
37.491
55.414
38.855
20.00


3227
LYS
HA
35.958
53.951
40.781
20.00


3228
LYS
1HB
35.782
52.475
38.241
20.00


3229
LYS
2HB
36.164
54.118
37.857
20.00


3230
LYS
1HG
34.004
54.112
37.648
20.00


3231
LYS
2HG
34.101
54.839
39.226
20.00


3232
LYS
1HD
33.656
52.326
40.073
20.00


3233
LYS
2HD
33.287
51.993
38.414
20.00


3234
LYS
1HE
31.446
53.975
38.749
20.00


3235
LYS
2HE
31.667
53.627
40.417
20.00


3236
LYS
1HZ
30.720
51.336
39.961
20.00


3237
LYS
2HZ
30.445
51.758
38.364
20.00


3238
LYS
3HZ
29.655
52.552
39.548
20.00


3239
VAL
N
38.441
52.045
39.435
13.89


3240
VAL
CA
39.117
50.767
39.646
11.86


3241
VAL
C
39.668
50.735
41.109
11.86


3242
VAL
O
39.382
49.808
41.856
11.98


3243
VAL
CB
40.222
50.455
38.595
12.00


3244
VAL
CG1
39.714
50.431
37.083
11.88


3245
VAL
CG2
40.882
49.143
38.956
12.37


3246
VAL
H
38.644
52.666
38.678
20.00


3247
VAL
HA
38.347
50.001
39.562
20.00


3248
VAL
HB
40.980
51.236
38.654
20.00


3249
VAL
1HG1
39.334
51.404
36.781
20.00


3250
VAL
2HG1
38.911
49.717
36.936
20.00


3251
VAL
3HG1
40.521
50.193
36.388
20.00


3252
VAL
1HG2
40.141
48.344
38.985
20.00


3253
VAL
2HG2
41.338
49.168
39.940
20.00


3254
VAL
3HG2
41.657
48.868
38.246
20.00


3255
ARG
N
40.409
51.870
41.447
12.93


3256
ARG
CA
40.873
52.261
42.832
14.48


3257
ARG
C
39.825
52.066
43.972
16.45


3258
ARG
O
39.966
51.141
44.744
17.22


3259
ARG
CB
41.467
53.625
42.820
13.76


3260
ARG
CG
42.889
53.536
42.265
12.22


3261
ARG
CD
43.652
54.811
42.463
13.67


3262
ARG
NE
45.033
54.629
42.060
15.68


3263
ARG
CZ
46.003
55.526
42.281
14.21


3264
ARG
NH
45.760
56.603
42.913
12.91


3265
ARG
NH2
47.224
55.411
41.884
12.03


3266
ARG
H
40.563
52.500
40.699
20.00


3267
ARG
HA
41.629
51.519
43.075
20.00


3268
ARG
1HB
41.495
54.037
43.832
20.00


3269
ARG
2HB
40.831
54.268
42.232
20.00


3270
ARG
1HG
42.853
53.277
41.206
20.00


3271
ARG
2HG
43.451
52.741
42.750
20.00


3272
ARG
1HD
43.664
55.063
43.522
20.00


3273
ARG
2HD
43.212
55.649
41.915
20.00


3274
ARG
HE
45.320
53.862
41.467
20.00


3275
ARG
1HH1
46.502
57.215
43.201
20.00


3276
ARG
2HH1
44.822
56.812
43.169
20.00


3277
ARG
1HH2
47.930
56.047
42.164
20.00


3278
ARG
2HH2
47.472
54.665
41.247
20.00


3279
GLU
N
38.745
52.856
43.977
16.23


3280
GLU
CA
37.684
52.766
45.003
16.92


3281
GLU
C
37.252
51.348
45.300
16.63


3282
GLU
O
36.916
50.971
46.419
17.05


3283
GLU
CB
36.444
53.545
44.582
21.77


3284
GLU
CG
36.799
54.907
43.984
30.11


3285
GLU
CD
37.027
55.961
44.992
37.62


3286
GLU
OE1
36.553
57.060
44.734
42.75


3287
GLU
OE2
37.678
55.675
46.010
39.25


3288
GLU
H
38.672
53.569
43.277
20.00


3289
GLU
HA
38.104
53.180
45.920
20.00


3290
GLU
1HB
35.743
53.654
45.404
20.00


3291
GLU
2HB
35.911
53.001
43.806
20.00


3292
GLU
1HG
36.049
55.234
43.267
20.00


3293
GLU
2HG
37.756
54.964
43.507
20.00


3294
SER
N
37.245
50.596
44.208
16.50


3295
SER
CA
36.586
49.299
44.192
17.63


3296
SER
C
37.276
48.308
45.115
20.41


3297
SER
O
36.752
47.306
45.551
21.90


3298
SER
CB
36.543
48.757
42.749
14.84


3299
SER
OG
37.770
47.902
42.522
13.92


3300
SER
H
37.593
51.010
43.365
20.00


3301
SER
HA
35.572
49.436
44.561
20.00


3302
SER
1HB
36.155
49.519
42.003
20.00


3303
SER
2HB
35.639
48.112
42.750
20.00


3304
SER
HG
38.700
48.252
42.358
20.00


3305
GLY
N
38.524
48.565
45.371
20.72


3306
GLY
CA
39.194
47.651
46.288
20.75


3307
GLY
C
40.089
46.595
45.636
22.62


3308
GLY
O
40.792
45.813
46.284
25.75


3309
GLY
H
38.903
49.440
45.055
20.00


3310
GLY
1HA
38.508
47.150
46.966
20.00


3311
GLY
2HA
39.722
48.329
46.930
20.00


3312
SER
N
40.027
46.568
44.280
20.77


3313
SER
CA
40.726
45.501
43.613
20.37


3314
SER
C
42.153
45.729
43.531
22.30


3315
SER
O
42.854
44.771
43.336
22.94


3316
SER
CB
40.220
45.343
42.184
17.21


3317
SER
OG
38.756
45.469
42.138
16.17


3318
SER
H
39.321
47.129
43.860
20.00


3319
SER
HA
40.564
44.582
44.184
20.00


3320
SER
1HB
40.511
44.313
41.903
20.00


3321
SER
2HB
40.832
45.875
41.397
20.00


3322
SER
HG
38.200
46.170
42.594
20.00


3323
LEU
N
42.580
46.968
43.678
22.44


3324
LEU
CA
44.021
47.151
43.601
25.58


3325
LEU
C
44.758
46.978
44.971
29.18


3326
LEU
O
45.885
47.472
45.142
34.54


3327
LEU
CB
44.227
48.551
43.032
23.62


3328
LEU
CG
43.771
48.613
41.595
22.66


3329
LEU
CD1
44.790
47.909
40.682
23.63


3330
LEU
CD2
43.739
50.030
41.191
25.59


3331
LEU
H
41.920
47.692
43.869
20.00


3332
LEU
HA
44.457
46.425
42.916
20.00


3333
LEU
1HB
45.272
48.860
43.086
20.00


3334
LEU
2HB
43.668
49.264
43.642
20.00


3335
LEU
HG
42.768
48.203
41.473
20.00


3336
LEU
1HD1
44.838
46.837
40.861
20.00


3337
LEU
2HD1
45.797
48.314
40.814
20.00


3338
LEU
3HD1
44.523
48.057
39.636
20.00


3339
LEU
1HD2
44.730
50.484
41.260
20.00


3340
LEU
2HD2
43.082
50.610
41.825
20.00


3341
LEU
3HD2
43.390
50.156
40.166
20.00


3342
SER
N
44.047
46.362
45.949
27.88


3343
SER
CA
44.527
46.315
47.294
28.98


3344
SER
C
45.268
45.026
47.535
29.17


3345
SER
O
44.928
44.000
46.945
29.28


3346
SER
CB
43.294
46.473
48.203
29.56


3347
SER
OG
42.391
47.648
47.851
38.82


3348
SER
H
43.142
45.971
45.753
20.00


3349
SER
HA
45.282
47.090
47.412
20.00


3350
SER
1HB
43.680
46.480
49.240
20.00


3351
SER
2HB
42.704
45.533
48.129
20.00


3352
SER
HG
42.660
48.585
47.609
20.00


3353
PRO
N
46.350
45.122
48.386
28.99


3354
PRO
CA
47.235
44.009
48.606
28.15


3355
PRO
C
46.665
42.947
49.550
27.34


3356
PRO
O
47.292
41.932
49.843
28.43


3357
PRO
CB
48.430
44.664
49.261
29.14


3358
PRO
CG
47.828
45.786
50.081
28.91


3359
PRO
CD
46.762
46.306
49.144
28.77


3360
PRO
HA
47.507
43.522
47.670
20.00


3361
PRO
1HB
49.098
45.079
48.505
20.00


3362
PRO
2HB
49.021
43.976
49.861
20.00


3363
PRO
1HG
47.380
45.394
50.989
20.00


3364
PRO
2HG
48.563
46.532
50.377
20.00


3365
PRO
1HD
47.199
47.044
48.471
20.00


3366
PRO
2HD
45.931
46.753
49.695
20.00


3367
GLU
N
45.457
43.150
49.997
25.89


3368
GLU
CA
44.871
41.988
50.605
27.19


3369
GLU
C
44.368
41.012
49.552
26.00


3370
GLU
O
43.942
39.916
49.893
25.89


3371
GLU
CB
43.911
42.425
51.728
33.55


3372
GLU
CG
42.550
43.115
51.372
41.02


3373
GLU
CD
42.705
44.505
50.654
47.74


3374
GLU
OE1
43.847
45.031
50.685
49.25


3375
GLU
OE2
41.702
45.025
50.090
51.04


3376
GLU
H
44.923
43.947
49.758
20.00


3377
GLU
HA
45.628
41.417
51.145
20.00


3378
GLU
1HB
44.457
43.059
52.424
20.00


3379
GLU
2HB
43.665
41.517
52.278
20.00


3380
GLU
1HG
41.959
43.265
52.272
20.00


3381
GLU
2HG
41.958
42.466
50.731
20.00


3382
HIS
N
44.471
41.415
48.248
21.92


3383
HIS
CA
44.127
40.631
47.048
18.96


3384
HIS
C
45.367
40.200
46.240
17.83


3385
HIS
O
46.450
40.745
46.401
17.07


3386
HIS
CB
43.211
41.449
46.115
20.94


3387
HIS
CG
41.922
41.788
46.796
20.70


3388
HIS
ND1
41.464
43.035
47.020
22.42


3389
HIS
CD2
40.920
40.898
47.210
19.89


3390
HIS
CE1
40.213
42.908
47.536
18.97


3391
HIS
NE2
39.847
41.615
47.661
19.93


3392
HIS
H
44.691
42.370
48.072
20.00


3393
HIS
HA
43.622
39.722
47.371
20.00


3394
HIS
1HB
42.958
40.907
45.199
20.00


3395
HIS
2HB
43.680
42.390
45.807
20.00


3396
HIS
HD1
41.918
43.894
46.893
20.00


3397
HIS
HD2
41.004
39.819
47.163
20.00


3398
HIS
HE1
39.593
43.730
47.851
20.00


3399
GLY
N
45.184
39.221
45.302
16.31


3400
GLY
CA
46.302
39.054
44.354
14.07


3401
GLY
C
46.385
40.252
43.419
12.35


3402
GLY
O
45.650
41.217
43.559
13.46


3403
GLY
H
44.287
38.802
45.246
20.00


3404
GLY
1HA
46.107
38.168
43.769
20.00


3405
GLY
2HA
47.243
38.952
44.893
20.00


3406
PRO
N
47.313
40.254
42.476
11.56


3407
PRO
CA
47.457
41.398
41.621
13.06


3408
PRO
C
46.319
41.572
40.614
12.70


3409
PRO
O
45.791
40.570
40.113
13.68


3410
PRO
CB
48.793
41.186
40.861
11.82


3411
PRO
CG
49.194
39.809
41.186
12.42


3412
PRO
CD
48.405
39.318
42.377
11.92


3413
PRO
HA
47.521
42.314
42.213
20.00


3414
PRO
1HB
49.530
41.880
41.216
20.00


3415
PRO
2HB
48.701
41.370
39.795
20.00


3416
PRO
1HG
48.850
39.180
40.380
20.00


3417
PRO
2HG
50.270
39.657
41.272
20.00


3418
PRO
1HD
49.014
39.338
43.284
20.00


3419
PRO
2HD
48.052
38.297
42.234
20.00


3420
VAL
N
45.973
42.849
40.334
12.70


3421
VAL
CA
44.929
42.963
39.339
12.91


3422
VAL
C
45.483
42.510
37.953
13.19


3423
VAL
O
46.621
42.728
37.620
11.64


3424
VAL
CB
44.496
44.421
39.253
13.06


3425
VAL
CG1
43.349
44.731
38.248
14.25


3426
VAL
CG2
45.666
45.279
38.707
13.39


3427
VAL
H
46.382
43.579
40.884
20.00


3428
VAL
HA
44.101
42.315
39.632
20.00


3429
VAL
HB
44.216
44.757
40.258
20.00


3430
VAL
1HG1
42.439
44.202
38.530
20.00


3431
VAL
2HG1
43.570
44.460
37.215
20.00


3432
VAL
3HG1
43.120
45.801
38.259
20.00


3433
VAL
1HG2
45.922
45.076
37.665
20.00


3434
VAL
2HG2
46.576
45.157
39.298
20.00


3435
VAL
3HG2
45.433
46.341
38.734
20.00


3436
VAL
N
44.602
41.927
37.144
12.59


3437
VAL
CA
44.881
41.577
35.752
11.98


3438
VAL
O
44.531
42.778
34.849
12.38


3439
VAL
O
43.397
43.158
34.785
15.24


3440
VAL
CB
44.176
40.272
35.374
9.51


3441
VAL
CG1
44.743
39.059
36.135
9.49


3442
VAL
CG2
44.361
39.925
33.910
10.06


3443
VAL
H
43.709
41.713
37.540
20.00


3444
VAL
HA
45.954
41.413
35.671
20.00


3445
VAL
HB
43.115
40.379
35.597
20.00


3446
VAL
1HG1
44.479
39.140
37.183
20.00


3447
VAL
2HG1
45.824
38.965
36.047
20.00


3448
VAL
3HG1
44.325
38.113
35.792
20.00


3449
VAL
1HG2
45.410
39.826
33.635
20.00


3450
VAL
2HG2
43.899
40.660
33.252
20.00


3451
VAL
3HG2
43.873
38.976
33.702
20.00


3452
VAL
N
45.479
43.359
34.121
10.51


3453
VAL
CA
45.213
44.321
33.091
10.15


3454
VAL
C
45.520
43.549
31.813
11.07


3455
VAL
O
46.535
42.885
31.627
11.12


3456
VAL
CB
46.096
45.556
33.342
9.24


3457
VAL
CG1
46.058
45.910
34.877
8.57


3458
VAL
CG2
45.692
46.835
32.573
9.28


3459
VAL
H
46.407
43.018
34.253
20.00


3460
VAL
HA
44.159
44.590
33.110
20.00


3461
VAL
HB
47.120
45.295
33.080
20.00


3462
VAL
1HG1
46.514
45.136
35.496
20.00


3463
VAL
2HG1
45.048
46.086
35.240
20.00


3464
VAL
3HG1
46.642
46.804
35.079
20.00


3465
VAL
1HG2
44.720
47.202
32.917
20.00


3466
VAL
2HG2
45.588
46.664
31.520
20.00


3467
VAL
3HG2
46.421
47.627
32.738
20.00


3468
HIS
N
44.588
43.703
30.899
10.38


3469
HIS
CA
44.843
43.345
29.524
8.48


3470
HIS
C
44.257
44.454
28.566
10.06


3471
HIS
O
43.285
45.158
28.830
9.96


3472
HIS
CB
44.287
41.924
29.313
8.91


3473
HIS
CG
42.824
41.948
28.937
8.64


3474
HIS
ND1
42.370
41.918
27.656
7.44


3475
HIS
CD2
41.783
41.815
29.793
8.51


3476
HIS
CE1
41.082
41.735
27.708
9.19


3477
HIS
NE2
40.730
41.677
28.984
11.46


3478
HIS
H
43.749
44.180
31.164
20.00


3479
HIS
HA
45.921
43.222
29.367
20.00


3480
HIS
1HB
44.424
41.327
30.215
20.00


3481
HIS
2HB
44.812
41.427
28.502
20.00


3482
HIS
HD1
42.926
41.960
26.851
20.00


3483
HIS
HD2
41.793
41.781
30.873
20.00


3484
HIS
HE1
40.391
41.585
26.885
20.00


3485
CYS
N
44.901
44.539
27.410
10.31


3486
CYS
CA
44.335
45.149
26.196
8.62


3487
CYS
C
44.351
44.032
25.182
9.41


3488
CYS
O
44.133
42.849
25.460
9.11


3489
CYS
CB
45.153
46.362
25.753
9.94


3490
CYS
SG
47.021
46.150
25.889
10.94


3491
CYS
H
45.698
43.931
27.402
20.00


3492
CYS
HA
43.311
45.451
26.378
20.00


3493
CYS
1HB
44.769
47.265
26.233
20.00


3494
CYS
2HB
44.846
46.673
24.780
20.00


3495
CYS
HG
47.564
46.018
24.675
20.00


3496
SER
N
44.663
44.316
23.984
9.15


3497
SER
CA
44.722
43.139
23.130
8.78


3498
SER
C
46.105
42.359
23.239
8.55


3499
SER
O
46.217
41.128
23.347
8.15


3500
SER
CB
44.389
43.699
21.683
7.93


3501
SER
OG
44.662
42.684
20.631
8.26


3502
SER
H
44.850
45.208
23.621
20.00


3503
SER
HA
43.891
42.482
23.434
20.00


3504
SER
1HB
45.102
44.543
21.547
20.00


3505
SER
2HB
43.440
44.339
21.661
20.00


3506
SER
HG
44.215
41.792
20.609
20.00


3507
ALA
N
47.234
43.166
23.239
8.61


3508
ALA
CA
48.571
42.556
23.451
7.66


3509
ALA
C
49.048
42.526
24.949
8.82


3510
ALA
O
49.906
41.719
25.386
11.75


3511
ALA
CB
49.495
43.448
22.703
7.00


3512
ALA
H
47.101
44.074
22.832
20.00


3513
ALA
HA
48.580
41.555
23.021
20.00


3514
ALA
1HB
49.449
44.478
23.062
20.00


3515
ALA
2HB
49.221
43.481
21.650
20.00


3516
ALA
3HB
50.531
43.112
22.754
20.00


3517
GLY
N
48.451
43.474
25.731
8.66


3518
GLY
CA
48.838
43.523
27.166
8.32


3519
GLY
C
50.020
44.449
27.521
9.76


3520
GLY
O
50.750
44.217
28.493
10.12


3521
GLY
H
47.716
43.998
25.323
20.00


3522
GLY
1HA
49.118
42.517
27.472
20.00


3523
GLY
2HA
47.962
43.705
27.760
20.00


3524
ILE
N
50.209
45.476
26.649
11.14


3525
ILE
CA
51.393
46.367
26.588
12.07


3526
ILE
C
51.104
47.859
26.189
10.76


3527
ILE
O
51.483
48.766
26.906
12.85


3528
ILE
CB
52.535
45.757
25.705
8.68


3529
ILE
CG1
52.223
45.596
24.220
9.17


3530
ILE
CG2
52.925
44.361
26.249
8.98


3531
ILE
CD1
53.481
45.306
23.388
7.46


3532
ILE
H
49.535
45.515
25.921
20.00


3533
ILE
HA
51.746
46.417
27.621
20.00


3534
ILE
HB
53.406
46.400
25.807
20.00


3535
ILE
1HG1
51.822
46.511
23.805
20.00


3536
ILE
2HG1
51.482
44.821
24.044
20.00


3537
ILE
1HG2
52.130
43.636
26.107
20.00


3538
ILE
2HG2
53.153
44.435
27.313
20.00


3539
ILE
3HG2
53.807
43.971
25.748
20.00


3540
ILE
1HD1
53.909
44.318
23.568
20.00


3541
ILE
2HD1
54.265
46.026
23.602
20.00


3542
ILE
3HD1
53.262
45.368
22.319
20.00


3543
GLY
N
50.417
48.135
25.062
10.38


3544
GLY
CA
50.161
49.536
24.720
9.10


3545
GLY
C
49.289
50.270
25.787
10.90


3546
GLY
O
49.707
51.067
26.645
10.20


3547
GLY
H
50.328
47.389
24.405
20.00


3548
GLY
1HA
49.709
49.560
23.740
20.00


3549
GLY
2HA
51.112
50.049
24.648
20.00


3550
ARG
N
48.015
49.955
25.638
11.01


3551
ARG
CA
47.000
50.422
26.563
10.63


3552
ARG
C
47.250
49.944
28.078
10.18


3553
ARG
O
47.128
50.731
28.993
10.97


3554
ARG
CB
45.607
50.070
26.013
9.12


3555
ARG
CG
45.144
50.880
24.746
9.78


3556
ARG
CD
43.773
50.426
24.185
7.58


3557
ARG
NE
44.049
49.233
23.356
8.89


3558
ARG
CZ
43.196
48.582
22.597
9.55


3559
ARG
NH1
41.972
48.921
22.463
10.16


3560
ARG
NH2
43.540
47.568
21.873
9.68


3561
ARG
H
47.708
49.447
24.827
20.00


3562
ARG
HA
47.003
51.506
26.576
20.00


3563
ARG
1HB
44.861
50.223
26.789
20.00


3564
ARG
2HB
45.634
49.021
25.746
20.00


3565
ARG
1HG
45.900
50.827
23.957
20.00


3566
ARG
2HG
45.132
51.924
25.011
20.00


3567
ARG
1HD
43.364
51.196
23.526
20.00


3568
ARG
2HD
43.068
50.217
24.981
20.00


3569
ARG
HE
45.007
48.990
23.182
20.00


3570
ARG
1HH1
41.396
48.399
21.816
20.00


3571
ARG
2HH1
41.590
49.702
22.945
20.00


3572
ARG
1HH2
42.793
47.113
21.366
20.00


3573
ARG
2HH2
44.482
47.294
21.669
20.00


3574
SER
N
47.594
48.689
28.346
10.07


3575
SER
CA
47.913
48.208
29.693
8.26


3576
SER
C
49.065
48.962
30.267
10.19


3577
SER
O
48.901
49.340
31.398
10.34


3578
SER
CB
48.033
46.638
29.836
8.89


3579
SER
OG
46.922
45.809
29.211
11.05


3580
SER
H
47.665
48.073
27.569
20.00


3581
SER
HA
47.089
48.557
30.322
20.00


3582
SER
1HB
48.069
46.443
30.939
20.00


3583
SER
2HB
49.068
46.298
29.561
20.00


3584
SER
HG
46.279
46.160
28.550
20.00


3585
GLY
N
50.182
49.229
29.505
10.44


3586
GLY
CA
51.325
49.953
30.078
8.60


3587
GLY
C
50.896
51.373
30.405
9.62


3588
GLY
O
51.139
51.879
31.498
11.83


3589
GLY
H
50.224
48.899
28.558
20.00


3590
GLY
1HA
52.103
49.991
29.311
20.00


3591
GLY
2HA
51.649
49.439
30.989
20.00


3592
THR
N
50.155
52.015
29.454
11.37


3593
THR
CA
49.632
53.367
29.813
10.02


3594
THR
C
48.846
53.501
31.196
11.10


3595
THR
O
49.111
54.330
32.043
9.82


3596
THR
CB
48.658
53.726
28.649
9.53


3597
THR
OG1
49.394
53.774
27.401
10.14


3598
THR
CG2
48.212
55.179
28.705
8.73


3599
THR
H
50.061
51.610
28.544
20.00


3600
THR
HA
50.475
54.060
29.842
20.00


3601
THR
HB
47.638
53.223
28.821
20.00


3602
THR
HG1
49.688
52.952
26.910
20.00


3603
THR
1HG2
49.090
55.745
28.772
20.00


3604
THR
2HG2
47.611
55.422
29.584
20.00


3605
THR
3HG2
47.726
55.537
27.806
20.00


3606
PHE
N
47.836
52.592
31.360
9.10


3607
PHE
CA
46.998
52.422
32.513
10.60


3608
PHE
C
47.763
52.282
33.849
10.58


3609
PHE
O
47.468
53.018
34.785
11.24


3610
PHE
CB
46.107
51.169
32.361
8.88


3611
PHE
CG
45.222
51.035
33.635
9.58


3612
PHE
CD1
43.998
51.687
33.724
11.54


3613
PHE
CD2
45.625
50.250
34.736
11.23


3614
PHE
CE1
43.198
51.577
34.840
6.44


3615
PHE
CE2
44.807
50.110
35.884
9.94


3616
PHE
CZ
43.575
50.768
35.919
6.47


3617
PHE
H
47.740
51.934
30.607
20.00


3618
PHE
HA
46.395
53.324
32.576
20.00


3619
PHE
1HB
46.680
50.256
32.197
20.00


3620
PHE
2HB
45.487
51.288
31.473
20.00


3621
PHE
HD1
43.670
52.276
32.877
20.00


3622
PHE
HD2
46.584
49.739
34.711
20.00


3623
PHE
HE1
42.263
52.121
34.876
20.00


3624
PHE
HE2
45.155
49.525
36.733
20.00


3625
PHE
HZ
42.947
50.692
36.793
20.00


3626
CYS
N
48.703
51.295
33.817
10.70


3627
CYS
CA
49.631
50.947
34.885
10.02


3628
CYS
C
50.699
52.006
35.192
10.89


3629
CYS
O
51.065
52.292
36.335
12.32


3630
CYS
CB
50.376
49.689
34.433
12.17


3631
CYS
SG
49.243
48.345
34.666
15.41


3632
CYS
H
48.709
50.767
32.964
20.00


3633
CYS
HA
49.055
50.755
35.790
20.00


3634
CYS
1HB
51.208
49.519
35.117
20.00


3635
CYS
2HB
50.793
49.726
33.426
20.00


3636
CYS
HG
48.768
48.009
33.459
20.00


3637
LEU
N
51.226
52.596
34.112
10.01


3638
LEU
CA
52.185
53.673
34.273
10.37


3639
LEU
C
51.674
54.833
35.143
10.12


3640
LEU
O
52.319
55.313
36.051
9.30


3641
LEU
CB
52.734
54.180
32.895
9.12


3642
LEU
CG
53.780
55.327
33.205
11.23


3643
LEU
CD1
54.197
56.096
31.977
11.32


3644
LEU
CD2
55.004
54.815
34.036
11.96


3645
LEU
H
50.866
52.331
33.223
20.00


3646
LEU
HA
53.005
53.241
34.825
20.00


3647
LEU
1HB
51.930
54.585
32.286
20.00


3648
LEU
2HB
53.201
53.374
32.332
20.00


3649
LEU
HG
53.317
56.100
33.819
20.00


3650
LEU
1HD1
53.342
56.567
31.505
20.00


3651
LEU
2HD1
54.636
55.435
31.232
20.00


3652
LEU
3HD1
54.937
56.849
32.198
20.00


3653
LEU
1HD2
55.470
53.966
33.544
20.00


3654
LEU
2HD2
54.680
54.473
35.013
20.00


3655
LEU
3HD2
55.757
55.589
34.178
20.00


3656
ALA
N
50.511
55.296
34.725
10.91


3657
ALA
CA
49.836
56.419
35.284
10.80


3658
ALA
C
49.353
56.116
36.768
11.33


3659
ALA
O
49.659
56.874
37.671
10.76


3660
ALA
CB
48.789
56.860
34.272
7.83


3661
ALA
H
50.129
54.843
33.918
20.00


3662
ALA
HA
50.597
57.196
35.359
20.00


3663
ALA
1HB
48.087
56.053
34.063
20.00


3664
ALA
2HB
49.263
57.110
33.316
20.00


3665
ALA
3HB
48.242
57.733
34.616
20.00


3666
ASP
N
48.709
54.939
37.028
11.75


3667
ASP
CA
48.530
54.419
38.415
11.91


3668
ASP
C
49.770
54.521
39.379
11.55


3669
ASP
O
49.711
55.168
40.421
11.95


3670
ASP
CB
47.928
52.991
38.350
10.16


3671
ASP
CG
47.508
52.440
39.753
13.48


3672
ASP
OD1
46.984
53.154
40.612
12.31


3673
ASP
OD2
47.716
51.287
40.031
12.63


3674
ASP
H
48.369
54.406
36.245
20.00


3675
ASP
HA
47.781
55.068
38.858
20.00


3676
ASP
1HB
48.599
52.290
37.857
20.00


3677
ASP
2HB
47.011
53.008
37.763
20.00


3678
THR
N
50.869
53.897
38.951
10.97


3679
THR
CA
52.060
53.792
39.783
11.02


3680
THR
C
52.733
55.095
39.943
11.79


3681
THR
O
53.143
55.434
41.062
11.99


3682
THR
CB
53.122
52.827
39.159
11.07


3683
THR
OG1
52.653
51.451
38.973
11.80


3684
THR
CG2
54.351
52.594
40.065
10.36


3685
THR
H
50.727
53.360
38.110
20.00


3686
THR
HA
51.787
53.543
40.811
20.00


3687
THR
HB
53.646
53.341
38.290
20.00


3688
THR
HG1
51.720
51.234
38.657
20.00


3689
THR
1HG2
54.046
52.144
41.006
20.00


3690
THR
2HG2
54.884
53.516
40.274
20.00


3691
THR
3HG2
55.051
51.906
39.588
20.00


3692
CYS
N
52.728
55.872
38.863
10.65


3693
CYS
CA
53.207
57.210
39.137
10.63


3694
CYS
C
52.322
58.003
40.111
12.96


3695
CYS
O
52.866
58.826
40.820
13.56


3696
CYS
CB
53.409
58.056
37.880
10.48


3697
CYS
SG
54.835
57.579
36.906
13.42


3698
CYS
H
52.373
55.549
37.978
20.00


3699
CYS
HA
54.197
57.134
39.592
20.00


3700
CYS
1HB
53.582
59.091
38.184
20.00


3701
CYS
2HB
52.512
58.066
37.258
20.00


3702
CYS
HG
54.517
56.537
36.129
20.00


3703
LEU
N
50.996
57.761
40.200
10.64


3704
LEU
CA
50.209
58.546
41.149
11.23


3705
LEU
C
50.345
57.934
42.558
12.65


3706
LEU
O
50.250
58.570
43.589
14.44


3707
LEU
CB
48.712
58.588
40.748
9.49


3708
LEU
CG
48.459
59.449
39.550
8.57


3709
LEU
CD1
48.546
60.918
39.903
10.68


3710
LEU
CD2
47.149
59.075
38.926
11.48


3711
LEU
H
50.585
57.122
39.545
20.00


3712
LEU
HA
50.594
59.563
41.168
20.00


3713
LEU
1HB
48.112
58.972
41.572
20.00


3714
LEU
2HB
48.360
57.578
40.552
20.00


3715
LEU
HG
49.224
59.256
38.808
20.00


3716
LEU
1HD1
49.555
61.220
40.186
20.00


3717
LEU
2HD1
47.884
61.189
40.720
20.00


3718
LEU
3HD1
48.268
61.545
39.055
20.00


3719
LEU
1HD2
46.315
59.278
39.602
20.00


3720
LEU
2HD2
47.126
58.022
38.642
20.00


3721
LEU
3HD2
46.963
59.659
38.023
20.00


3722
LEU
N
50.587
56.660
42.564
13.24


3723
LEU
CA
50.835
56.004
43.863
12.90


3724
LEU
C
52.190
56.454
44.611
13.36


3725
LEU
O
52.395
56.408
45.830
15.00


3726
LEU
CB
50.904
54.505
43.469
12.90


3727
LEU
CG
49.835
53.569
43.939
17.31


3728
LEU
CD1
49.263
53.990
45.326
17.90


3729
LEU
CD2
50.526
52.220
43.957
17.91


3730
LEU
H
50.646
56.184
41.684
20.00


3731
LEU
HA
49.999
56.251
44.523
20.00


3732
LEU
1HB
51.908
54.136
43.644
20.00


3733
LEU
2HB
50.832
54.426
42.388
20.00


3734
LEU
HG
49.006
53.536
43.238
20.00


3735
LEU
1HD1
48.585
54.836
45.275
20.00


3736
LEU
2HD1
50.070
54.266
46.010
20.00


3737
LEU
3HD1
48.730
53.181
45.816
20.00


3738
LEU
1HD2
51.425
52.244
44.573
20.00


3739
LEU
2HD2
50.823
51.905
42.956
20.00


3740
LEU
3HD2
49.881
51.463
44.393
20.00


3741
LEU
N
53.129
56.820
43.760
14.06


3742
LEU
CA
54.476
57.023
44.220
15.83


3743
LEU
C
54.440
58.400
44.768
15.86


3744
LEU
O
54.749
58.682
45.911
15.48


3745
LEU
CB
55.357
56.970
42.985
15.91


3746
LEU
CG
56.668
56.200
43.023
18.29


3747
LEU
CD1
56.873
55.755
41.585
20.36


3748
LEU
CD2
56.800
55.028
43.983
16.23


3749
LEU
H
52.886
56.679
42.799
20.00


3750
LEU
HA
54.733
56.275
44.971
20.00


3751
LEU
1HB
55.586
57.948
42.562
20.00


3752
LEU
2HB
54.761
56.546
42.184
20.00


3753
LEU
HG
57.472
56.891
43.272
20.00


3754
LEU
1HD1
56.867
56.632
40.928
20.00


3755
LEU
2HD1
56.101
55.069
41.240
20.00


3756
LEU
3HD1
57.836
55.256
41.439
20.00


3757
LEU
1HD2
55.882
54.460
43.936
20.00


3758
LEU
2HD2
56.954
55.352
45.011
20.00


3759
LEU
3HD2
57.613
54.361
43.694
20.00


3760
MET
N
53.976
59.242
43.877
14.06


3761
MET
CA
53.624
60.606
44.191
16.10


3762
MET
C
52.765
60.733
45.517
18.37


3763
MET
O
53.079
61.547
46.384
17.82


3764
MET
CB
53.022
61.097
42.848
17.90


3765
MET
CG
52.600
62.534
42.880
22.88


3766
MET
SD
52.133
63.122
41.275
27.93


3767
MET
CE
53.674
62.882
40.484
21.01


3768
MET
H
53.802
58.889
42.947
20.00


3769
MET
HA
54.574
61.137
44.355
20.00


3770
MET
1HB
52.142
60.514
42.589
20.00


3771
MET
2HB
53.726
60.932
42.040
20.00


3772
MET
1HG
53.414
63.117
43.298
20.00


3773
MET
2HG
51.765
62.692
43.563
20.00


3774
MET
1HE
53.737
61.868
40.089
20.00


3775
MET
2HE
54.533
63.102
41.116
20.00


3776
MET
3HE
53.709
63.582
39.649
20.00


3777
ASP
N
51.796
59.845
45.706
17.66


3778
ASP
CA
51.046
59.817
46.959
18.72


3779
ASP
C
51.866
59.517
48.249
20.72


3780
ASP
O
51.506
60.010
49.317
18.46


3781
ASP
CB
49.865
58.833
46.789
15.77


3782
ASP
C
48.692
59.223
47.720
15.78


3783
ASP
OD1
47.921
60.098
47.335
15.30


3784
ASP
OD2
48.573
58.745
48.849
12.03


3785
ASP
H
51.489
59.265
44.954
20.00


3786
ASP
HA
50.641
60.814
47.092
20.00


3787
ASP
1HB
50.143
57.792
46.991
20.00


3788
ASP
2HB
49.523
58.841
45.757
20.00


3789
LYS
N
52.983
58.760
48.131
22.67


3790
LYS
CA
53.674
58.145
49.290
26.79


3791
LYS
C
54.931
58.920
49.795
27.91


3792
LYS
O
55.952
58.446
50.319
27.25


3793
LYS
CB
53.901
56.634
49.079
31.63


3794
LYS
CG
55.221
56.174
48.432
36.21


3795
LYS
CD
55.564
54.732
48.920
41.15


3796
LYS
CE
54.502
53.672
48.501
45.83


3797
LYS
NZ
54.382
52.509
49.411
48.52


3798
LYS
H
53.168
58.421
47.202
20.00


3799
LYS
HA
52.971
58.231
50.127
20.00


3800
LYS
1HB
53.037
56.222
48.565
20.00


3801
LYS
2HB
53.878
56.200
50.076
20.00


3802
LYS
1HG
56.072
56.800
48.691
20.00


3803
LYS
2HG
55.142
56.208
47.346
20.00


3804
LYS
1HD
55.694
54.725
50.001
20.00


3805
LYS
2HD
56.528
54.416
48.507
20.00


3806
LYS
1HE
54.738
53.304
47.496
20.00


3807
LYS
2HE
53.519
54.136
48.398
20.00


3808
LYS
1HZ
54.131
52.810
50.372
20.00


3809
LYS
2HZ
55.273
51.969
49.417
20.00


3810
LYS
3HZ
53.633
51.882
49.045
20.00


3811
ARG
N
54.783
60.192
49.561
29.18


3812
ARG
CA
55.920
61.072
49.744
30.25


3813
ARG
C
55.412
62.476
49.597
28.51


3814
ARG
O
55.983
63.400
50.172
29.83


3815
ARG
CB
57.138
60.726
48.833
35.96


3816
ARG
CG
56.825
60.702
47.353
35.60


3817
ARG
CD
57.971
60.140
46.489
39.72


3818
ARG
NE
58.346
58.740
46.746
44.72


3819
ARG
CZ
59.252
58.052
45.985
49.49


3820
ARG
NH1
59.736
58.571
44.823
46.55


3821
ARG
NH2
59.631
56.831
46.444
54.27


3822
ARG
H
53.921
60.398
49.096
20.00


3823
ARG
HA
56.222
60.959
50.792
20.00


3824
ARG
1HB
57.517
59.753
49.136
20.00


3825
ARG
2HB
57.954
61.419
49.015
20.00


3826
ARG
1HG
56.572
61.699
46.997
20.00


3827
ARG
2HG
55.957
60.080
47.195
20.00


3828
ARG
1HD
58.897
60.700
46.658
20.00


3829
ARG
2HD
57.668
60.138
45.441
20.00


3830
ARG
HE
57.974
58.277
47.547
20.00


3831
ARG
1HH1
60.317
57.968
44.264
20.00


3832
ARG
2HH1
59.524
59.501
44.534
20.00


3833
ARG
1HH2
60.241
56.297
45.852
20.00


3834
ARG
2HH2
59.320
56.463
47.308
20.00


3835
LYS
N
54.299
62.635
48.843
24.03


3836
LYS
CA
53.709
63.975
48.683
22.66


3837
LYS
C
54.836
65.076
48.313
22.19


3838
LYS
O
54.746
66.296
48.531
22.54


3839
LYS
CB
52.828
64.382
49.905
23.45


3840
LYS
CG
51.703
63.412
50.390
20.10


3841
LYS
CD
50.532
63.202
49.448
20.71


3842
LYS
CE
49.505
62.232
50.059
17.94


3843
LYS
NZ
48.450
61.958
49.071
27.72


3844
LYS
H
53.968
61.880
48.276
20.00


3845
LYS
HA
53.071
63.873
47.806
20.00


3846
LYS
1HB
52.363
65.342
49.684
20.00


3847
LYS
2HB
53.494
64.560
50.747
20.00


3848
LYS
1HG
51.304
63.828
51.315
20.00


3849
LYS
2HG
52.136
62.454
50.672
20.00


3850
LYS
1HD
50.884
62.812
48.489
20.00


3851
LYS
2HD
50.052
64.161
49.235
20.00


3852
LYS
1HE
49.049
62.670
50.950
20.00


3853
LYS
2HE
49.952
61.283
50.363
20.00


3854
LYS
1HZ
48.810
61.313
48.331
20.00


3855
LYS
2HZ
48.109
62.817
48.578
20.00


3856
LYS
3HZ
47.647
61.409
49.432
20.00


3857
ASP
N
55.889
64.482
47.680
21.48


3858
ASP
CA
56.806
65.251
46.882
22.85


3859
ASP
C
56.543
64.944
45.345
21.41


3860
ASP
O
57.198
64.103
44.713
21.48


3861
ASP
CB
58.216
64.968
47.416
25.58


3862
ASP
CG
59.244
65.767
46.566
29.64


3863
ASP
OD1
58.862
66.819
45.964
31.77


3864
ASP
OD2
60.408
65.344
46.549
30.41


3865
ASP
H
56.060
63.508
47.768
20.00


3866
ASP
HA
56.609
66.305
47.057
20.00


3867
ASP
1HB
58.465
63.918
47.556
20.00


3868
ASP
2HB
58.277
65.369
48.429
20.00


3869
PRO
N
55.539
65.638
44.744
20.58


3870
PRO
CA
55.308
65.416
43.295
22.04


3871
PRO
C
56.569
65.307
42.347
24.22


3872
PRO
O
56.572
64.547
41.372
22.77


3873
PRO
CB
54.441
66.653
42.852
23.82


3874
PRO
CG
53.958
67.350
44.156
22.76


3875
PRO
CD
54.861
66.824
45.284
22.17


3876
PRO
HA
54.784
64.489
43.157
20.00


3877
PRO
1HB
53.643
66.360
42.176
20.00


3878
PRO
2HB
55.022
67.367
42.285
20.00


3879
PRO
1HG
53.966
68.430
44.056
20.00


3880
PRO
2HG
52.945
67.022
44.344
20.00


3881
PRO
1HD
54.292
66.563
46.162
20.00


3882
PRO
2HD
55.589
67.586
45.557
20.00


3883
SER
N
57.644
66.017
42.810
26.49


3884
SER
CA
58.744
66.328
41.960
29.21


3885
SER
C
59.732
65.218
41.913
28.16


3886
SER
O
60.301
64.849
40.890
30.98


3887
SER
CB
59.304
67.616
42.594
32.36


3888
SER
OG
58.637
68.913
42.285
37.57


3889
SER
H
57.630
66.394
43.738
20.00


3890
SER
HA
58.429
66.385
40.908
20.00


3891
SER
1HB
60.351
67.694
42.232
20.00


3892
SER
2HB
59.521
67.454
43.682
20.00


3893
SER
HG
57.670
69.067
42.060
20.00


3894
SER
N
59.925
64.613
43.043
25.94


3895
SER
CA
60.809
63.466
42.969
23.97


3896
SER
C
60.407
62.308
41.968
23.07


3897
SER
O
61.251
61.419
41.868
23.41


3898
SER
CB
60.695
62.845
44.395
24.53


3899
SER
OG
59.325
62.461
44.856
26.18


3900
SER
H
59.459
64.900
43.888
20.00


3901
SER
HA
61.810
63.811
42.723
20.00


3902
SER
1HB
61.331
63.448
45.113
20.00


3903
SER
2HB
61.358
61.949
44.388
20.00


3904
SER
HG
58.514
63.013
44.586
20.00


3905
VAL
N
59.176
62.231
41.306
22.45


3906
VAL
CA
58.834
61.027
40.461
21.20


3907
VAL
C
59.182
61.249
38.947
21.26


3908
VAL
O
58.675
62.163
38.320
22.49


3909
VAL
CB
57.391
60.434
40.620
22.58


3910
VAL
CG1
56.451
60.386
39.363
20.76


3911
VAL
CG2
56.695
61.029
41.828
17.17


3912
VAL
H
58.588
63.040
41.291
20.00


3913
VAL
HA
59.500
60.233
40.807
20.00


3914
VAL
HB
57.535
59.380
40.863
20.00


3915
VAL
1HG1
56.888
59.787
38.559
20.00


3916
VAL
2HG1
56.252
61.381
38.973
20.00


3917
VAL
3HG1
55.488
59.919
39.577
20.00


3918
VAL
1HG2
56.539
62.101
41.733
20.00


3919
VAL
2HG2
57.252
60.803
42.729
20.00


3920
VAL
3HG2
55.729
60.556
41.956
20.00


3921
ASP
N
60.034
60.370
38.393
19.92


3922
ASP
CA
60.422
60.486
37.014
19.98


3923
ASP
C
59.593
59.489
36.190
17.61


3924
ASP
O
59.810
58.291
36.270
18.51


3925
ASP
CB
61.968
60.298
36.922
21.39


3926
ASP
CG
62.632
60.452
35.517
25.31


3927
ASP
OD1
62.006
60.671
34.458
23.58


3928
ASP
OD2
63.846
60.336
35.498
32.08


3929
ASP
H
60.462
59.701
38.992
20.00


3930
ASP
HA
60.181
61.487
36.644
20.00


3931
ASP
1HB
62.267
59.369
37.393
20.00


3932
ASP
2HB
62.408
61.078
37.534
20.00


3933
ILE
N
58.641
60.060
35.429
18.00


3934
ILE
CA
57.715
59.212
34.684
16.17


3935
ILE
C
58.457
58.121
33.908
16.20


3936
ILE
O
58.158
56.962
33.989
16.71


3937
ILE
CB
56.682
60.059
33.831
18.69


3938
ILE
CG1
55.862
61.009
34.788
20.07


3939
ILE
CG2
55.633
59.144
33.082
16.13


3940
ILE
CD1
54.494
61.498
34.162
22.35


3941
ILE
H
58.643
61.059
35.410
20.00


3942
ILE
HA
57.154
58.675
35.450
20.00


3943
ILE
HB
57.226
60.649
33.091
20.00


3944
ILE
1HG1
56.474
61.858
35.081
20.00


3945
ILE
2HG1
55.628
60.471
35.709
20.00


3946
ILE
1HG2
55.008
58.573
33.774
20.00


3947
ILE
2HG2
56.178
58.446
32.443
20.00


3948
ILE
3HG2
54.982
59.699
32.406
20.00


3949
ILE
1HD1
53.818
60.694
33.876
20.00


3950
ILE
2HD1
54.710
62.086
33.280
20.00


3951
ILE
3HD1
53.924
62.104
34.865
20.00


3952
LYS
N
59.488
58.562
33.158
15.61


3953
LYS
CA
60.319
57.703
32.288
16.12


3954
LYS
C
61.173
56.727
33.130
15.62


3955
LYS
O
61.228
55.568
32.799
15.12


3956
LYS
CB
61.147
58.457
31.166
18.84


3957
LYS
CG
60.600
59.764
30.558
31.31


3958
LYS
CD
61.795
60.577
29.985
37.73


3959
LYS
CE
62.746
61.132
31.087
43.40


3960
LYS
NZ
62.754
62.577
31.255
47.06


3961
LYS
H
59.666
59.540
33.256
20.00


3962
LYS
HA
59.593
57.072
31.780
20.00


3963
LYS
1HB
61.394
57.754
30.371
20.00


3964
LYS
2HB
62.114
58.664
31.609
20.00


3965
LYS
1HG
60.123
60.303
31.374
20.00


3966
LYS
2HG
59.834
59.586
29.806
20.00


3967
LYS
1HD
61.613
61.325
29.225
20.00


3968
LYS
2HD
62.379
59.879
29.384
20.00


3969
LYS
1HE
63.770
60.795
30.916
20.00


3970
LYS
2HE
62.462
60.714
32.058
20.00


3971
LYS
1HZ
61.799
62.973
31.456
20.00


3972
LYS
2HZ
63.031
63.140
30.419
20.00


3973
LYS
3HZ
63.326
62.866
32.070
20.00


3974
LYS
N
61.763
57.189
34.225
16.19


3975
LYS
CA
62.257
56.242
35.200
17.17


3976
LYS
C
61.293
55.010
35.671
15.81


3977
LYS
O
61.750
53.857
35.780
13.38


3978
LYS
CB
62.721
57.021
36.420
21.47


3979
LYS
CG
63.685
56.179
37.285
26.41


3980
LYS
CD
64.794
57.072
37.807
32.75


3981
LYS
CE
65.626
57.849
36.734
37.01


3982
LYS
NZ
67.041
58.078
37.149
41.44


3983
LYS
H
61.705
58.168
34.443
20.00


3984
LYS
HA
63.127
55.786
34.726
20.00


3985
LYS
1HB
61.887
57.362
37.030
20.00


3986
LYS
2HB
63.231
57.909
36.056
20.00


3987
LYS
1HG
64.127
55.380
36.694
20.00


3988
LYS
2HG
63.149
55.685
38.097
20.00


3989
LYS
1HD
65.457
56.465
38.425
20.00


3990
LYS
2HD
64.355
57.817
38.475
20.00


3991
LYS
1HE
65.173
58.818
36.541
20.00


3992
LYS
2HE
65.625
57.311
35.781
20.00


3993
LYS
1HZ
67.519
57.178
37.364
20.00


3994
LYS
2HZ
67.048
58.692
37.990
20.00


3995
LYS
3HZ
67.545
58.575
36.382
20.00


3996
VAL
N
59.985
55.323
35.959
15.38


3997
VAL
CA
59.007
54.265
36.251
13.40


3998
VAL
C
58.622
53.424
35.039
12.42


3999
VAL
O
58.570
52.215
35.094
12.19


4000
VAL
CB
57.954
54.563
37.383
17.62


4001
VAL
CG1
56.568
53.984
37.220
13.70


4002
VAL
CG2
57.966
55.998
37.910
14.26


4003
VAL
H
59.750
56.303
35.924
20.00


4004
VAL
HA
59.627
53.531
36.757
20.00


4005
VAL
HB
58.323
54.004
38.246
20.00


4006
VAL
1HG1
56.577
52.930
36.941
20.00


4007
VAL
2HG1
56.042
54.545
36.459
20.00


4008
VAL
3HG1
55.990
54.074
38.141
20.00


4009
VAL
1HG2
57.755
56.693
37.096
20.00


4010
VAL
2HG2
58.937
56.269
38.321
20.00


4011
VAL
3HG2
57.210
56.147
38.681
20.00


4012
LEU
N
58.433
54.033
33.899
11.53


4013
LEU
CA
58.144
53.234
32.728
12.42


4014
LEU
C
59.278
52.236
32.445
11.91


4015
LEU
O
59.058
51.051
32.366
10.65


4016
LEU
CB
57.743
54.157
31.624
12.94


4017
LEU
CG
57.326
53.410
30.304
14.51


4018
LEU
CD1
57.086
54.408
29.182
14.86


4019
LEU
CD2
56.160
52.386
30.503
12.64


4020
LEU
H
58.437
55.031
33.911
20.00


4021
LEU
HA
57.258
52.666
32.990
20.00


4022
LEU
1HB
58.593
54.808
31.418
20.00


4023
LEU
2HB
56.941
54.822
31.950
20.00


4024
LEU
HG
58.192
52.818
30.000
20.00


4025
LEU
1HD1
57.963
55.014
29.049
20.00


4026
LEU
2HD1
56.240
55.060
29.390
20.00


4027
LEU
3HD1
56.896
53.878
28.248
20.00


4028
LEU
1HD2
55.276
52.909
30.864
20.00


4029
LEU
2HD2
56.404
51.623
31.245
20.00


4030
LEU
3HD2
55.893
51.869
29.585
20.00


4031
LEU
N
60.504
52.731
32.420
14.10


4032
LEU
CA
61.690
51.872
32.395
13.57


4033
LEU
C
61.761
50.752
33.479
11.98


4034
LEU
O
62.002
49.612
33.082
10.15


4035
LEU
CB
62.918
52.796
32.471
15.92


4036
LEU
CG
63.686
53.177
31.132
18.96


4037
LEU
CD1
64.024
54.658
31.092
18.76


4038
LEU
CD2
63.078
52.694
29.832
20.15


4039
LEU
H
60.599
53.726
32.457
20.00


4040
LEU
HA
61.655
51.323
31.457
20.00


4041
LEU
1HB
63.669
52.330
33.103
20.00


4042
LEU
2HB
62.658
53.693
33.033
20.00


4043
LEU
HG
64.658
52.680
31.172
20.00


4044
LEU
1HD1
64.621
54.977
31.950
20.00


4045
LEU
2HD1
63.112
55.255
31.098
20.00


4046
LEU
3HD1
64.604
54.927
30.204
20.00


4047
LEU
1HD2
62.022
52.950
29.855
20.00


4048
LEU
2HD2
63.159
51.613
29.727
20.00


4049
LEU
3HD2
63.545
53.169
28.966
20.00


4050
ASP
N
61.560
51.032
34.837
13.06


4051
ASP
CA
61.390
49.905
35.801
12.70


4052
ASP
C
60.231
48.923
35.403
11.44


4053
ASP
O
60.321
47.695
35.475
11.16


4054
ASP
CB
61.278
50.344
37.304
15.05


4055
ASP
CG
62.123
49.288
38.082
23.08


4056
ASP
OD1
63.364
49.262
38.000
22.88


4057
ASP
OD2
61.586
48.379
38.689
24.92


4058
ASP
H
61.491
51.996
35.102
20.00


4059
ASP
HA
62.301
49.314
35.656
20.00


4060
ASP
1HB
60.255
50.372
37.670
20.00


4061
ASP
2HB
61.732
51.315
37.466
20.00


4062
MET
N
59.093
49.516
34.944
13.08


4063
MET
CA
58.001
48.656
34.411
12.59


4064
MET
C
58.462
47.656
33.363
10.76


4065
MET
O
58.113
46.455
33.408
9.86


4066
MET
CB
56.904
49.483
33.836
14.18


4067
MET
CG
55.903
49.698
34.916
20.95


4068
MET
SD
54.280
50.357
34.340
25.25


4069
MET
CE
54.062
51.043
35.991
24.15


4070
MET
H
59.129
50.515
34.915
20.00


4071
MET
HA
57.666
48.053
35.256
20.00


4072
MET
1HB
56.398
49.008
33.008
20.00


4073
MET
2HB
57.229
50.450
33.479
20.00


4074
MET
1HG
56.386
50.456
35.537
20.00


4075
MET
2HG
55.734
48.842
35.576
20.00


4076
MET
1HE
54.838
51.743
36.278
20.00


4077
MET
2HE
54.045
50.220
36.708
20.00


4078
MET
3HE
53.126
51.565
35.960
20.00


4079
ARG
N
59.282
48.214
32.437
11.81


4080
ARG
CA
59.642
47.419
31.226
14.09


4081
ARG
C
60.637
46.252
31.489
14.19


4082
ARG
O
60.925
45.526
30.551
15.37


4083
ARG
CB
59.943
48.311
29.993
15.27


4084
ARG
CG
59.098
49.556
29.941
20.41


4085
ARG
CD
58.376
49.966
28.632
22.57


4086
ARG
NE
59.200
50.017
27.449
21.00


4087
ARG
CZ
58.839
50.296
26.192
19.36


4088
ARG
NH1
57.852
51.031
25.801
17.30


4089
ARG
NH2
59.579
49.731
25.327
15.47


4090
ARG
H
59.531
49.173
32.573
20.00


4091
ARG
HA
58.706
46.936
30.961
20.00


4092
ARG
1HB
59.788
47.723
29.092
20.00


4093
ARG
2HB
60.999
48.599
29.991
20.00


4094
ARG
1HG
59.729
50.392
30.254
20.00


4095
ARG
2HG
58.294
49.528
30.682
20.00


4096
ARG
1HD
57.908
50.943
28.745
20.00


4097
ARG
2HD
57.606
49.239
28.396
20.00


4098
ARG
HE
60.107
49.639
27.637
20.00


4099
ARG
1HH1
57.601
51.294
24.882
20.00


4100
ARG
2HH1
57.261
51.372
26.542
20.00


4101
ARG
1HH2
59.524
49.940
24.352
20.00


4102
ARG
2HH2
60.246
49.058
25.646
20.00


4103
LYS
N
61.164
46.114
32.773
12.82


4104
LYS
CA
61.935
44.941
33.256
11.88


4105
LYS
C
61.085
43.713
33.410
11.52


4106
LYS
O
61.593
42.577
33.421
12.87


4107
LYS
CB
62.641
45.126
34.625
10.90


4108
LYS
CG
63.618
46.277
34.601
10.61


4109
LYS
CD
64.058
46.712
35.985
16.89


4110
LYS
CE
65.109
47.798
35.884
18.25


4111
LYS
NZ
65.603
48.012
37.220
18.64


4112
LYS
H
60.974
46.858
33.419
20.00


4113
LYS
HA
62.681
44.732
32.484
20.00


4114
LYS
1HB
63.115
44.215
34.984
20.00


4115
LYS
2HB
61.880
45.373
35.364
20.00


4116
LYS
1HG
63.158
47.138
34.122
20.00


4117
LYS
2HG
64.500
45.961
34.042
20.00


4118
LYS
1HD
64.460
45.868
36.534
20.00


4119
LYS
2HD
63.195
47.069
36.549
20.00


4120
LYS
1HE
64.731
48.741
35.473
20.00


4121
LYS
2HE
65.940
47.473
35.260
20.00


4122
LYS
1HZ
65.673
47.094
37.707
20.00


4123
LYS
2HZ
64.909
48.549
37.785
20.00


4124
LYS
3HZ
66.557
48.423
37.253
20.00


4125
PHE
N
59.784
43.979
33.518
11.46


4126
PHE
CA
58.890
42.872
33.793
10.66


4127
PHE
C
58.071
42.350
32.647
10.63


4128
PHE
O
57.810
41.174
32.624
11.08


4129
PHE
CB
57.941
43.342
34.873
10.87


4130
PHE
CG
58.702
43.716
36.137
10.74


4131
PHE
CD1
59.198
42.740
36.931
14.67


4132
PHE
CD2
58.946
45.007
36.493
13.16


4133
PHE
CE1
59.928
43.056
38.070
14.61


4134
PHE
CE2
59.709
45.342
37.584
11.84


4135
PHE
CZ
60.231
44.342
38.364
12.78


4136
PHE
H
59.498
44.933
33.611
20.00


4137
PHE
HA
59.449
41.996
34.159
20.00


4138
PHE
1HB
57.244
42.532
35.092
20.00


4139
PHE
2HB
57.356
44.185
34.502
20.00


4140
PHE
HD1
59.026
41.700
36.674
20.00


4141
PHE
HD2
58.541
45.812
35.888
20.00


4142
PHE
HE1
60.292
42.264
38.718
20.00


4143
PHE
HE2
59.892
46.384
37.839
20.00


4144
PHE
HZ
60.833
44.580
39.223
20.00


4145
ARG
N
57.637
43.234
31.729
11.78


4146
ARG
CA
56.999
42.971
30.403
11.12


4147
ARG
C
57.537
43.989
29.272
10.70


4148
ARG
O
57.754
45.168
29.450
11.00


4149
ARG
CB
55.450
43.030
30.422
9.05


4150
ARG
CG
54.720
42.312
29.233
8.54


4151
ARG
CD
53.173
42.198
29.472
8.35


4152
ARG
NE
52.329
41.703
28.413
8.45


4153
ARG
CZ
52.240
40.450
27.919
8.44


4154
ARG
NH1
52.939
39.527
28.425
8.74


4155
ARG
NH2
51.413
40.156
26.940
9.54


4156
ARG
H
57.860
44.166
32.007
20.00


4157
ARG
HA
57.284
41.962
30.171
20.00


4158
ARG
1HB
55.116
44.056
30.542
20.00


4159
ARG
2HB
55.154
42.528
31.341
20.00


4160
ARG
1HG
55.200
41.356
29.029
20.00


4161
ARG
2HG
54.899
42.903
28.332
20.00


4162
ARG
1HD
52.863
43.247
29.522
20.00


4163
ARG
2HD
52.834
41.843
30.446
20.00


4164
ARG
HE
51.722
42.406
28.035
20.00


4165
ARG
1HH1
52.806
38.586
28.112
20.00


4166
ARG
2HH1
53.602
39.812
29.109
20.00


4167
ARG
1HH2
51.312
39.214
26.626
20.00


4168
ARG
2HH2
50.878
40.883
26.495
20.00


4169
MET
N
57.716
43.404
28.075
11.10


4170
MET
CA
58.186
44.260
26.962
10.52


4171
MET
C
57.024
45.223
26.500
12.21


4172
MET
O
55.843
44.858
26.471
11.69


4173
MET
CB
58.606
43.362
25.796
12.40


4174
MET
CG
57.434
42.486
25.214
13.12


4175
MET
SD
57.895
41.619
23.717
12.49


4176
MET
CE
59.286
40.641
24.231
14.52


4177
MET
H
57.157
42.590
27.946
20.00


4178
MET
HA
59.033
44.839
27.332
20.00


4179
MET
1HB
59.421
42.716
26.125
20.00


4180
MET
2HB
59.017
43.981
24.995
20.00


4181
MET
1HG
56.537
43.061
24.993
20.00


4182
MET
2HG
57.153
41.751
25.963
20.00


4183
MET
1HE
58.999
40.071
25.111
20.00


4184
MET
2HE
60.128
41.283
24.473
20.00


4185
MET
3HE
59.569
39.950
23.436
20.00


4186
GLY
N
57.448
46.438
26.060
11.82


4187
GLY
CA
56.696
47.240
25.071
10.69


4188
GLY
C
55.505
47.941
25.724
11.80


4189
GLY
O
54.605
48.408
25.044
11.81


4190
GLY
H
58.395
46.587
26.326
20.00


4191
GLY
1HA
56.379
46.563
24.277
20.00


4192
GLY
2HA
57.369
47.983
24.659
20.00


4193
LEU
N
55.644
48.052
27.083
11.43


4194
LEU
CA
54.762
48.854
27.881
11.39


4195
LEU
C
54.798
50.309
27.386
12.20


4196
LEU
O
55.819
51.000
27.369
12.24


4197
LEU
CB
55.125
48.664
29.353
10.83


4198
LEU
CG
55.153
47.177
29.826
9.47


4199
LEU
CD1
53.979
46.390
29.211
9.16


4200
LEU
CD2
55.106
46.987
31.376
10.38


4201
LEU
H
56.255
47.429
27.563
20.00


4202
LEU
HA
53.765
48.452
27.684
20.00


4203
LEU
1HB
54.363
49.187
29.928
20.00


4204
LEU
2HB
56.038
49.177
29.650
20.00


4205
LEU
HG
56.074
46.731
29.458
20.00


4206
LEU
1HD1
54.146
46.270
28.145
20.00


4207
LEU
2HD1
53.059
46.958
29.330
20.00


4208
LEU
3HD1
53.845
45.402
29.632
20.00


4209
LEU
1HD2
54.239
47.489
31.812
20.00


4210
LEU
2HD2
56.013
47.373
31.822
20.00


4211
LEU
3HD2
55.039
45.931
31.632
20.00


4212
ILE
N
53.611
50.747
26.925
10.54


4213
ILE
CA
53.352
51.904
26.078
11.17


4214
ILE
C
53.942
51.707
24.614
13.75


4215
ILE
O
55.152
51.525
24.341
13.91


4216
ILE
CB
53.775
53.199
26.797
11.11


4217
ILE
CG1
53.323
53.232
28.236
9.13


4218
ILE
CG2
53.534
54.509
25.973
14.38


4219
ILE
CD1
53.085
54.633
28.731
8.65


4220
ILE
H
52.857
50.110
27.076
20.00


4221
ILE
HA
52.300
51.849
25.895
20.00


4222
ILE
HB
54.854
53.154
26.854
20.00


4223
ILE
1HG1
54.057
52.753
28.875
20.00


4224
ILE
2HG1
52.434
52.641
28.395
20.00


4225
ILE
1HG2
52.489
54.771
26.013
20.00


4226
ILE
2HG2
53.837
54.423
24.931
20.00


4227
ILE
3HG2
54.073
55.352
26.405
20.00


4228
ILE
1HD1
52.339
55.011
28.055
20.00


4229
ILE
2HD1
53.956
55.277
28.718
20.00


4230
ILE
3HD1
52.642
54.642
29.720
20.00


4231
GLN
N
52.962
51.794
23.698
13.18


4232
GLN
CA
53.199
51.506
22.275
12.31


4233
GLN
C
53.430
52.716
21.367
14.51


4234
GLN
O
53.955
52.560
20.262
14.93


4235
GLN
CB
52.144
50.560
21.736
12.10


4236
GLN
CG
52.439
49.160
22.274
13.08


4237
GLN
CD
53.546
48.547
21.425
14.33


4238
GLN
OE1
53.483
48.340
20.241
16.45


4239
GLN
NE2
54.621
48.324
22.095
11.97


4240
GLN
H
52.069
52.116
24.025
20.00


4241
GLN
HA
54.053
50.882
22.198
20.00


4242
GLN
1HB
52.148
50.567
20.649
20.00


4243
GLN
2HB
51.163
50.906
22.068
20.00


4244
GLN
1HG
51.565
48.532
22.129
20.00


4245
GLN
2HG
52.700
49.128
23.334
20.00


4246
GLN
1HE2
55.255
47.877
21.463
20.00


4247
GLN
2HE2
54.687
48.534
23.072
20.00


4248
THR
N
52.999
53.889
21.847
14.47


4249
THR
CA
53.293
55.112
21.160
13.82


4250
THR
C
53.795
56.277
22.022
15.31


4251
THR
O
53.504
56.378
23.202
15.21


4252
THR
CB
52.018
55.721
20.549
12.44


4253
THR
OG1
51.132
56.387
21.467
13.84


4254
THR
CG2
51.116
54.688
19.900
12.80


4255
THR
H
52.517
53.881
22.722
20.00


4256
THR
HA
54.032
54.925
20.382
20.00


4257
THR
HB
52.313
56.216
19.551
20.00


4258
THR
HG1
51.470
57.060
22.111
20.00


4259
THR
1HG2
50.910
53.814
20.510
20.00


4260
THR
2HG2
51.562
54.409
18.964
20.00


4261
THR
3HG2
50.153
55.136
19.640
20.00


4262
ALA
N
54.477
57.213
21.304
16.12


4263
ALA
CA
54.775
58.515
21.914
17.15


4264
ALA
C
53.591
59.401
22.373
17.06


4265
ALA
O
53.789
60.142
23.290
16.84


4266
ALA
CB
55.595
59.324
20.904
15.40


4267
ALA
H
54.845
56.937
20.420
20.00


4268
ALA
HA
55.376
58.310
22.799
20.00


4269
ALA
1HB
55.020
59.526
19.991
20.00


4270
ALA
2HB
56.466
58.733
20.623
20.00


4271
ALA
3HB
55.932
60.276
21.309
20.00


4272
ASP
N
52.372
59.361
21.793
16.67


4273
ASP
CA
51.253
60.117
22.425
16.05


4274
ASP
C
50.459
59.397
23.628
14.16


4275
ASP
O
49.950
60.007
24.564
13.25


4276
ASP
CB
50.285
60.449
21.279
16.36


4277
ASP
CG
49.302
61.573
21.733
18.91


4278
ASP
OD1
49.622
62.439
22.570
19.27


4279
ASP
OD2
48.176
61.536
21.255
19.47


4280
ASP
H
52.169
58.892
20.940
20.00


4281
ASP
HA
51.675
61.041
22.821
20.00


4282
ASP
1HB
49.700
59.570
21.004
20.00


4283
ASP
2HB
50.796
60.835
20.398
20.00


4284
GLN
N
50.509
58.059
23.612
12.74


4285
GLN
CA
50.357
57.350
24.885
12.47


4286
GLN
C
51.372
57.732
25.883
13.42


4287
GLN
O
50.983
57.853
27.011
13.68


4288
GLN
CB
50.268
55.796
24.870
10.94


4289
GLN
CG
49.003
55.278
24.131
10.93


4290
GLN
CD
49.169
53.862
23.674
11.89


4291
GLN
OE1
50.245
53.338
23.823
13.27


4292
GLN
NE2
48.120
53.148
23.278
10.17


4293
GLN
H
50.220
57.686
22.728
20.00


4294
GLN
HA
49.410
57.687
25.306
20.00


4295
GLN
1HB
50.120
55.691
25.933
20.00


4296
GLN
2HB
51.199
55.298
24.622
20.00


4297
GLN
1HG
48.722
55.880
23.275
20.00


4298
GLN
2HG
48.157
55.324
24.814
20.00


4299
GLN
1HE2
48.192
52.170
23.170
20.00


4300
GLN
2HE2
47.274
53.670
23.184
20.00


4301
LEU
N
52.632
57.962
25.482
15.21


4302
LEU
CA
53.622
58.317
26.460
13.64


4303
LEU
C
53.221
59.639
27.103
14.41


4304
LEU
O
53.197
59.793
28.299
15.65


4305
LEU
CB
55.040
58.373
25.963
12.86


4306
LEU
CG
55.940
58.940
27.044
13.02


4307
LEU
CD1
57.423
59.114
26.568
12.87


4308
LEU
CD2
55.803
58.093
28.344
12.32


4309
LEU
H
52.853
57.713
24.542
20.00


4310
LEU
HA
53.697
57.475
27.137
20.00


4311
LEU
1HB
55.109
58.990
25.075
20.00


4312
LEU
2HB
55.368
57.378
25.665
20.00


4313
LEU
HG
55.643
59.956
27.299
20.00


4314
LEU
1HD1
57.503
59.794
25.718
20.00


4315
LEU
2HD1
57.826
58.155
26.246
20.00


4316
LEU
3HD1
58.066
59.498
27.365
20.00


4317
LEU
1HD2
55.984
57.030
28.190
20.00


4318
LEU
2HD2
54.823
58.181
28.813
20.00


4319
LEU
3HD2
56.521
58.432
29.090
20.00


4320
ARG
N
52.940
60.581
26.220
13.43


4321
ARG
CA
52.516
61.919
26.552
13.38


4322
ARG
C
51.245
61.967
27.425
14.16


4323
ARG
O
51.086
62.719
28.402
14.64


4324
ARG
CB
52.251
62.603
25.232
13.46


4325
ARG
CG
51.762
64.060
25.435
13.29


4326
ARG
CD
51.576
64.868
24.119
16.52


4327
ARG
NE
51.522
66.299
24.432
20.17


4328
ARG
CZ
50.397
67.002
24.409
19.49


4329
ARG
NH1
49.216
66.446
24.187
20.88


4330
ARG
NH2
50.463
68.265
24.567
21.32


4331
ARG
H
53.137
60.365
25.265
20.00


4332
ARG
HA
53.333
62.403
27.095
20.00


4333
ARG
1HB
51.506
62.063
24.656
20.00


4334
ARG
2HB
53.170
62.609
24.642
20.00


4335
ARG
1HG
52.524
64.576
26.019
20.00


4336
ARG
2HG
50.846
64.108
26.022
20.00


4337
ARG
1HD
50.719
64.529
23.542
20.00


4338
ARG
2HD
52.437
64.758
23.467
20.00


4339
ARG
HE
52.358
66.829
24.622
20.00


4340
ARG
1HH1
48.378
66.959
24.120
20.00


4341
ARG
2HH1
49.238
65.453
24.060
20.00


4342
ARG
1HH2
49.696
68.881
24.571
20.00


4343
ARG
2HH2
51.389
68.673
24.644
20.00


4344
PHE
N
50.335
61.083
26.968
13.41


4345
PHE
CA
49.001
61.017
27.582
13.00


4346
PHE
C
49.112
60.777
29.110
12.42


4347
PHE
O
48.608
61.592
29.880
14.84


4348
PHE
CB
48.098
60.098
26.822
12.87


4349
PHE
CG
46.828
60.022
27.581
13.08


4350
PHE
CD1
45.801
60.881
27.276
15.82


4351
PHE
CD2
46.705
59.168
28.680
13.48


4352
PHE
CE1
44.667
60.910
28.097
14.88


4353
PHE
CE2
45.574
59.191
29.498
14.71


4354
PHE
CZ
44.540
60.071
29.199
13.48


4355
PHE
H
50.562
60.635
26.109
20.00


4356
PHE
HA
48.585
62.029
27.497
20.00


4357
PHE
1HB
48.536
59.108
26.759
20.00


4358
PHE
2HB
47.915
60.462
25.813
20.00


4359
PHE
HD1
45.882
61.539
26.423
20.00


4360
PHE
HD2
47.512
58.491
28.940
20.00


4361
PHE
HE1
43.859
61.581
27.846
20.00


4362
PHE
HE2
45.506
58.535
30.360
20.00


4363
PHE
HZ
43.642
60.078
29.799
20.00


4364
SER
N
49.969
59.763
29.464
12.86


4365
SER
CA
50.587
59.542
30.810
13.82


4366
SER
C
51.041
60.698
31.656
15.06


4367
SER
O
50.771
60.701
32.874
15.36


4368
SER
CB
51.858
58.721
30.716
11.50


4369
SER
OG
51.516
57.632
29.848
19.07


4370
SER
H
50.242
59.181
28.697
20.00


4371
SER
HA
49.818
59.037
31.402
20.00


4372
SER
1HB
52.010
58.296
31.729
20.00


4373
SER
2HB
52.852
59.284
30.654
20.00


4374
SER
HG
51.270
57.729
28.858
20.00


4375
TYR
N
51.813
61.593
31.024
14.37


4376
TYR
CA
52.267
62.766
31.766
13.98


4377
TYR
C
51.058
63.681
31.998
14.72


4378
TYR
O
50.967
64.337
33.005
16.92


4379
TYR
CB
53.229
63.600
30.917
15.56


4380
TYR
CG
54.652
63.274
30.954
15.10


4381
TYR
CD1
55.052
62.134
30.271
15.01


4382
TYR
CD2
55.620
64.132
31.549
16.69


4383
TYR
CE1
56.421
61.838
30.141
17.26


4384
TYR
CE2
57.005
63.819
31.493
17.79


4385
TYR
CZ
57.399
62.668
30.725
18.91


4386
TYR
OH
58.714
62.271
30.439
22.03


4387
TYR
H
51.999
61.445
30.050
20.00


4388
TYR
HA
52.676
62.473
32.734
20.00


4389
TYR
1HB
53.169
64.651
31.202
20.00


4390
TYR
2HB
52.902
63.592
29.873
20.00


4391
TYR
HD1
54.327
61.491
29.785
20.00


4392
TYR
HD2
55.300
65.033
32.057
20.00


4393
TYR
HE1
56.711
60.965
29.563
20.00


4394
TYR
HE2
57.650
64.487
32.074
20.00


4395
TYR
HH
59.145
62.947
29.940
20.00


4396
LEU
N
50.119
63.730
31.072
14.60


4397
LEU
CA
48.847
64.446
31.233
13.80


4398
LEU
C
47.979
63.736
32.311
13.84


4399
LEU
O
47.376
64.413
33.100
15.22


4400
LEU
CB
48.123
64.423
29.847
15.22


4401
LEU
CG
47.836
65.699
28.996
17.91


4402
LEU
CD1
47.984
65.297
27.542
17.36


4403
LEU
CD2
48.732
66.869
29.241
17.38


4404
LEU
H
50.299
63.237
30.217
20.00


4405
LEU
HA
49.052
65.467
31.565
20.00


4406
LEU
1HB
47.178
63.886
29.921
20.00


4407
LEU
2HB
48.719
63.775
29.209
20.00


4408
LEU
HG
46.811
66.008
29.196
20.00


4409
LEU
1HD1
47.280
64.485
27.341
20.00


4410
LEU
2HD1
48.978
64.923
27.304
20.00


4411
LEU
3HD1
47.734
66.112
26.869
20.00


4412
LEU
1HD2
49.761
66.547
29.286
20.00


4413
LEU
2HD2
48.501
67.327
30.203
20.00


4414
LEU
3HD2
48.593
67.645
28.487
20.00


4415
ALA
N
47.923
62.376
32.381
13.18


4416
ALA
CA
47.070
61.732
33.394
12.65


4417
ALA
C
47.647
61.860
34.804
14.16


4418
ALA
O
46.924
62.169
35.735
14.00


4419
ALA
CB
46.896
60.294
33.069
13.02


4420
ALA
H
48.404
61.889
31.656
20.00


4421
ALA
HA
46.109
62.245
33.400
20.00


4422
ALA
1HB
47.848
59.772
33.044
20.00


4423
ALA
2HB
46.427
60.175
32.093
20.00


4424
ALA
3HB
46.257
59.808
33.797
20.00


4425
VAL
N
48.993
61.669
34.953
11.78


4426
VAL
CA
49.638
61.928
36.266
12.53


4427
VAL
C
49.529
63.388
36.657
13.82


4428
VAL
O
49.106
63.654
37.760
12.86


4429
VAL
CB
51.060
61.470
36.199
11.66


4430
VAL
CG1
51.011
59.975
35.935
13.24


4431
VAL
CG2
51.884
61.820
37.450
9.92


4432
VAL
H
49.505
61.389
34.142
20.00


4433
VAL
HA
49.097
61.346
37.011
20.00


4434
VAL
HE
51.525
61.950
35.339
20.00


4435
VAL
1HG1
50.457
59.680
35.046
20.00


4436
VAL
2HG1
50.567
59.443
36.774
20.00


4437
VAL
3HG1
52.028
59.609
35.790
20.00


4438
VAL
1HG2
51.434
61.452
38.374
20.00


4439
VAL
2HG2
52.023
62.899
37.543
20.00


4440
VAL
3HG2
52.878
61.383
37.357
20.00


4441
ILE
N
49.859
64.316
35.726
12.29


4442
ILE
CA
49.777
65.753
36.099
13.94


4443
ILE
C
48.339
66.176
36.660
14.15


4444
ILE
O
48.117
66.660
37.773
14.06


4445
ILE
CB
50.394
66.654
34.959
13.50


4446
ILE
CG1
51.944
66.544
34.796
14.91


4447
ILE
CG2
50.076
68.142
35.160
12.74


4448
ILE
CD1
52.435
66.779
33.323
13.99


4449
ILE
H
50.221
64.029
34.834
20.00


4450
ILE
HA
50.451
65.871
36.951
20.00


4451
ILE
HB
49.927
66.358
34.020
20.00


4452
ILE
1HG1
52.222
65.531
35.081
20.00


4453
ILE
2HG1
52.448
67.206
35.500
20.00


4454
ILE
1HG2
50.457
68.501
36.112
20.00


4455
ILE
2HG2
49.002
68.322
35.154
20.00


4456
ILE
3HG2
50.501
68.767
34.372
20.00


4457
ILE
1HD1
52.530
67.849
33.137
20.00


4458
ILE
2HD1
51.774
66.409
32.552
20.00


4459
ILE
3HD1
53.420
66.336
33.174
20.00


4460
GLU
N
47.359
65.839
35.881
13.27


4461
GLU
CA
45.989
66.067
36.314
12.79


4462
GLU
C
45.607
65.346
37.640
14.22


4463
GLU
O
45.016
65.931
38.541
14.98


4464
GLU
CB
45.069
65.673
35.120
11.88


4465
GLU
CG
43.617
66.022
35.440
12.69


4466
GLU
CD
43.489
67.515
35.873
18.61


4467
GLU
OE1
44.197
68.391
35.267
19.68


4468
GLU
OE2
42.684
67.786
36.795
20.07


4469
GLU
H
47.536
65.473
34.961
20.00


4470
GLU
HA
45.923
67.146
36.510
20.00


4471
GLU
1HB
45.179
64.633
34.870
20.00


4472
GLU
2HB
45.379
66.212
34.239
20.00


4473
GLU
1HG
43.215
65.380
36.227
20.00


4474
GLU
2HG
42.978
65.886
34.565
20.00


4475
GLY
N
46.045
64.072
37.760
14.10


4476
GLY
CA
45.654
63.221
38.876
11.35


4477
GLY
C
46.321
63.593
40.191
12.42


4478
GLY
O
45.815
63.292
41.292
14.09


4479
GLY
H
46.512
63.723
36.945
20.00


4480
GLY
1HA
45.949
62.203
38.620
20.00


4481
GLY
2HA
44.571
63.247
38.973
20.00


4482
ALA
N
47.519
64.244
40.018
12.11


4483
ALA
CA
48.374
64.823
41.082
13.24


4484
ALA
C
47.582
65.702
41.977
14.50


4485
ALA
O
47.596
65.589
43.194
15.74


4486
ALA
CB
49.490
65.703
40.494
12.85


4487
ALA
H
47.815
64.323
39.062
20.00


4488
ALA
HA
48.781
63.986
41.661
20.00


4489
ALA
1HB
49.117
66.579
39.973
20.00


4490
ALA
2HB
50.058
65.139
39.757
20.00


4491
ALA
3HB
50.202
66.027
41.246
20.00


4492
LYS
N
46.816
66.546
41.296
15.43


4493
LYS
CA
45.724
67.345
41.899
17.97


4494
LYS
C
44.931
66.779
43.125
18.17


4495
LYS
O
44.899
67.351
44.214
16.72


4496
LYS
CB
44.741
67.668
40.789
17.36


4497
LYS
CG
45.473
68.507
39.735
20.89


4498
LYS
CD
44.411
69.357
39.059
19.35


4499
LYS
CE
44.941
70.273
37.899
21.45


4500
LYS
NZ
43.854
70.561
36.916
28.58


4501
LYS
H
46.970
66.537
40.302
20.00


4502
LYS
HA
46.194
68.257
42.271
20.00


4503
LYS
1HB
43.929
68.238
41.230
20.00


4504
LYS
2HB
44.281
66.774
40.403
20.00


4505
LYS
1HG
46.030
67.909
39.021
20.00


4506
LYS
2HG
46.191
69.182
40.190
20.00


4507
LYS
1HD
43.864
69.945
39.793
20.00


4508
LYS
2HD
43.678
68.654
38.678
20.00


4509
LYS
1HE
45.750
69.766
37.367
20.00


4510
LYS
2HE
45.330
71.199
38.323
20.00


4511
LYS
1HZ
42.957
70.859
37.339
20.00


4512
LYS
2HZ
43.637
69.601
36.519
20.00


4513
LYS
3HZ
44.134
71.121
36.095
20.00


4514
PHE
N
44.281
65.638
42.830
17.06


4515
PHE
CA
43.646
64.836
43.843
17.26


4516
PHE
C
44.714
64.518
44.920
17.65


4517
PHE
O
44.482
64.738
46.105
17.35


4518
PHE
CB
42.997
63.581
43.127
16.04


4519
PHE
CG
42.385
62.573
44.092
18.17


4520
PHE
CD1
43.226
61.617
44.720
18.77


4521
PHE
CD2
41.030
62.660
44.476
17.46


4522
PHE
CE1
42.767
60.863
45.818
18.56


4523
PHE
CE2
40.577
61.903
45.587
17.26


4524
PHE
CZ
41.444
61.051
46.279
16.76


4525
PHE
H
44.444
65.270
41.908
20.00


4526
PHE
HA
42.892
65.451
44.341
20.00


4527
PHE
1HB
43.750
63.045
42.548
20.00


4528
PHE
2HB
42.235
63.919
42.431
20.00


4529
PHE
HD1
44.244
61.511
44.366
20.00


4530
PHE
HD2
40.363
63.332
43.956
20.00


4531
PHE
HE1
43.447
60.182
46.317
20.00


4532
PHE
HE2
39.540
61.973
45.889
20.00


4533
PHE
HZ
41.096
60.520
47.152
20.00


4534
ILE
N
45.904
64.058
44.464
17.16


4535
ILE
CA
46.963
63.619
45.424
16.95


4536
ILE
C
47.403
64.740
46.364
18.22


4537
ILE
O
47.734
64.521
47.537
19.58


4538
ILE
CB
48.233
63.056
44.686
16.65


4539
ILE
CG1
47.877
61.897
43.715
15.20


4540
ILE
CG2
49.381
62.644
45.664
17.33


4541
ILE
CD1
47.124
60.747
44.386
16.00


4542
ILE
H
46.085
64.029
43.475
20.00


4543
ILE
HA
46.533
62.830
46.038
20.00


4544
ILE
HB
48.696
63.820
44.061
20.00


4545
ILE
1HG1
48.782
61.500
43.247
20.00


4546
ILE
2HG1
47.269
62.310
42.913
20.00


4547
ILE
1HG2
49.052
61.908
46.381
20.00


4548
ILE
2HG2
49.782
63.508
46.200
20.00


4549
ILE
3HG2
50.229
62.212
45.127
20.00


4550
ILE
1HD1
46.267
61.066
44.967
20.00


4551
ILE
2HD1
47.811
60.254
45.053
20.00


4552
ILE
3HD1
46.779
60.010
43.663
20.00


4553
MET
N
47.484
65.937
45.795
17.76


4554
MET
CA
48.123
67.010
46.548
17.15


4555
MET
C
47.180
67.601
47.549
18.59


4556
MET
O
47.634
68.088
48.582
18.92


4557
MET
CB
48.913
67.951
45.663
18.33


4558
MET
CG
50.089
67.168
45.027
18.10


4559
MET
SD
51.391
66.428
46.158
22.98


4560
MET
CE
51.905
67.914
47.025
22.14


4561
MET
H
47.175
66.080
44.861
20.00


4562
MET
HA
48.874
66.553
47.202
20.00


4563
MET
1HB
49.285
68.791
46.230
20.00


4564
MET
2HB
48.257
68.389
44.906
20.00


4565
MET
1HG
50.607
67.834
44.333
20.00


4566
MET
2HG
49.687
66.363
44.396
20.00


4567
MET
1HE
51.085
68.420
47.548
20.00


4568
MET
2HE
52.319
68.603
46.291
20.00


4569
MET
3HE
52.687
67.673
47.749
20.00


4570
GLY
N
45.872
67.378
47.277
17.81


4571
GLY
CA
44.850
67.320
48.361
19.24


4572
GLY
C
43.474
67.982
48.080
18.12


4573
GLY
O
42.634
68.149
48.984
18.31


4574
GLY
H
45.672
66.962
46.387
20.00


4575
GLY
1HA
45.269
67.841
49.231
20.00


4576
GLY
2HA
44.716
66.282
48.674
20.00


4577
ASP
N
43.290
68.369
46.814
16.53


4578
ASP
CA
41.961
68.826
46.372
17.00


4579
ASP
C
41.035
67.607
46.048
18.13


4580
ASP
O
40.855
67.207
44.903
19.06


4581
ASP
CB
42.133
69.714
45.111
18.82


4582
ASP
CG
40.838
69.926
44.250
20.22


4583
ASP
OD1
39.720
69.692
44.750
19.51


4584
ASP
OD2
40.968
70.317
43.089
23.56


4585
ASP
H
44.012
68.210
46.144
20.00


4586
ASP
HA
41.478
69.396
47.157
20.00


4587
ASP
1HB
42.844
69.226
44.444
20.00


4588
ASP
2HB
42.546
70.691
45.349
20.00


4589
SER
N
40.427
66.964
47.031
18.73


4590
SER
CA
39.684
65.767
46.555
16.96


4591
SER
C
38.438
66.178
45.684
18.39


4592
SER
O
37.753
65.300
45.151
18.33


4593
SER
CB
39.548
64.762
47.784
17.13


4594
SER
OG
40.769
64.296
48.566
14.25


4595
SER
H
40.606
67.273
47.975
20.00


4596
SER
HA
40.219
65.218
45.768
20.00


4597
SER
1HB
38.927
63.897
47.443
20.00


4598
SER
2HB
38.817
65.230
48.491
20.00


4599
SER
HG
41.719
64.490
48.317
20.00


4600
SER
N
38.161
67.528
45.516
17.50


4601
SER
CA
37.016
68.024
44.673
18.74


4602
SER
C
37.183
67.715
43.164
17.75


4603
SER
O
36.183
67.406
42.477
16.68


4604
SER
CB
36.747
69.546
44.774
19.67


4605
SER
OG
37.500
70.494
43.897
21.88


4606
SER
H
38.797
68.224
45.866
20.00


4607
SER
HA
36.131
67.483
45.019
20.00


4608
SER
1HB
36.605
69.852
45.852
20.00


4609
SER
2HB
35.674
69.626
44.497
20.00


4610
SER
HG
38.484
70.378
43.663
20.00


4611
VAL
N
38.473
67.708
42.702
17.27


4612
VAL
CA
38.680
67.191
41.319
18.22


4613
VAL
C
37.910
65.970
40.883
18.73


4614
VAL
O
37.472
65.906
39.737
19.63


4615
VAL
CB
40.132
66.911
40.897
20.69


4616
VAL
CG1
40.884
66.073
41.910
17.79


4617
VAL
CG2
40.868
68.222
40.572
23.70


4618
VAL
H
39.207
68.134
43.257
20.00


4619
VAL
HA
38.305
67.980
40.690
20.00


4620
VAL
HB
40.169
66.379
39.947
20.00


4621
VAL
1HG1
40.410
65.103
42.049
20.00


4622
VAL
2HG1
40.897
66.580
42.855
20.00


4623
VAL
3HG1
41.920
65.935
41.604
20.00


4624
VAL
1HG2
41.042
68.758
41.495
20.00


4625
VAL
2HG2
40.304
68.883
39.916
20.00


4626
VAL
3HG2
41.836
68.034
40.111
20.00


4627
GLN
N
37.827
64.997
41.788
18.28


4628
GLN
CA
37.407
63.664
41.383
19.78


4629
GLN
C
35.957
63.564
40.980
23.25


4630
GLN
O
35.635
62.870
40.010
25.12


4631
GLN
CB
37.684
62.612
42.412
20.56


4632
GLN
CG
37.171
61.233
41.947
24.84


4633
GLN
CD
37.628
60.156
42.928
27.26


4634
GLN
OE1
38.497
60.357
43.777
31.04


4635
GLN
NE2
37.005
59.010
42.735
29.42


4636
GLN
H
38.155
65.203
42.714
20.00


4637
GLN
HA
37.983
63.430
40.496
20.00


4638
GLN
1HB
37.199
62.866
43.353
20.00


4639
GLN
2HB
38.752
62.567
42.609
20.00


4640
GLN
1HG
37.541
60.972
40.956
20.00


4641
GLN
2HG
36.077
61.187
41.899
20.00


4642
GLN
1HE2
37.189
58.293
43.411
20.00


4643
GLN
2HE2
36.335
58.854
42.017
20.00


4644
ASP
N
35.132
64.360
41.665
25.31


4645
ASP
CA
33.794
64.542
41.078
27.02


4646
ASP
C
33.714
65.515
39.851
25.79


4647
ASP
O
33.010
65.234
38.884
25.32


4648
ASP
CB
32.728
64.363
42.176
35.78


4649
ASP
CG
32.232
62.848
42.252
44.92


4650
ASP
OD1
33.060
61.924
42.012
50.04


4651
ASP
OD2
31.014
62.626
42.502
50.59


4652
ASP
H
35.428
64.744
42.538
20.00


4653
ASP
HA
33.606
63.669
40.453
20.00


4654
ASP
1HB
31.871
64.981
41.929
20.00


4655
ASP
2HB
33.104
64.706
43.143
20.00


4656
GLN
N
34.626
66.532
39.807
23.38


4657
GLN
CA
34.903
67.171
38.484
24.32


4658
GLN
C
35.209
66.229
37.269
23.16


4659
GLN
O
34.689
66.444
36.165
21.27


4660
GLN
CB
35.989
68.248
38.513
28.00


4661
GLN
CG
35.765
69.233
39.647
35.72


4662
GLN
CD
37.011
70.084
39.806
43.13


4663
GLN
OE1
37.614
70.466
38.814
48.57


4664
GLN
NE2
37.399
70.384
41.059
43.82


4665
GLN
H
35.105
66.754
40.660
20.00


4666
GLN
HA
33.969
67.668
38.222
20.00


4667
GLN
1HB
36.001
68.784
37.562
20.00


4668
GLN
2HB
36.973
67.792
38.594
20.00


4669
GLN
1HG
35.574
68.757
40.601
20.00


4670
GLN
2HG
34.922
69.879
39.419
20.00


4671
GLN
1HE2
38.245
70.918
41.061
20.00


4672
GLN
2HE2
36.969
70.145
41.925
20.00


4673
TRP
N
36.067
65.207
37.463
20.29


4674
TRP
CA
36.319
64.264
36.366
19.31


4675
TRP
C
35.089
63.487
35.918
19.07


4676
TRP
O
34.861
63.193
34.736
19.20


4677
TRP
CB
37.263
63.169
36.885
19.26


4678
TRP
CG
38.589
63.776
37.213
15.65


4679
TRP
CD1
39.188
64.909
36.656
14.94


4680
TRP
CD2
39.483
63.209
38.143
15.85


4681
TRP
NE1
40.412
65.088
37.205
15.54


4682
TRP
CE2
40.619
64.068
38.133
15.86


4683
TRP
CE3
39.390
62.115
38.989
14.86


4684
TRP
CZ2
41.699
63.722
38.904
16.78


4685
TRP
CZ3
40.479
61.761
39.786
14.37


4686
TRP
CH2
41.631
62.585
39.740
15.56


4687
TRP
H
36.508
65.153
38.360
20.00


4688
TRP
HA
36.722
64.799
35.513
20.00


4689
TRP
1HB
37.452
62.427
36.116
20.00


4690
TRP
2HB
36.849
62.663
37.759
20.00


4691
TRP
HD1
38.745
65.543
35.900
20.00


4692
TRP
HE1
41.059
65.811
37.001
20.00


4693
TRP
HE3
38.490
61.508
38.989
20.00


4694
TRP
HZ2
42.571
64.373
38.864
20.00


4695
TRP
HZ3
40.436
60.909
40.460
20.00


4696
TRP
HH2
42.485
62.328
40.349
20.00


4697
LYS
N
34.338
63.136
36.976
21.19


4698
LYS
CA
33.082
62.421
36.730
24.17


4699
LYS
C
32.154
63.264
35.758
25.28


4700
LYS
O
31.736
62.892
34.656
26.15


4701
LYS
CB
32.453
62.137
38.108
26.43


4702
LYS
CG
31.329
61.095
38.057
32.00


4703
LYS
CD
30.909
60.906
39.490
38.87


4704
LYS
CE
29.764
59.913
39.692
45.47


4705
LYS
NZ
29.279
60.040
41.099
51.74


4706
LYS
H
34.648
63.302
37.917
20.00


4707
LYS
HA
33.334
61.452
36.303
20.00


4708
LYS
1HB
32.101
63.055
38.569
20.00


4709
LYS
2HB
33.239
61.739
38.752
20.00


4710
LYS
1HG
31.674
60.151
37.631
20.00


4711
LYS
2HG
30.495
61.432
37.435
20.00


4712
LYS
1HD
30.615
61.873
39.902
20.00


4713
LYS
2HD
31.768
60.576
40.078
20.00


4714
LYS
1HE
30.136
58.898
39.499
20.00


4715
LYS
2HE
28.947
60.090
38.984
20.00


4716
LYS
1HZ
29.033
61.040
41.269
20.00


4717
LYS
2HZ
30.103
59.869
41.719
20.00


4718
LYS
3HZ
28.496
59.397
41.317
20.00


4719
GLU
N
32.050
64.521
36.209
26.22


4720
GLU
CA
31.455
65.533
35.365
27.87


4721
GLU
C
32.006
65.577
33.869
26.53


4722
GLU
O
31.332
65.367
32.866
30.42


4723
GLU
CB
31.542
66.807
36.263
34.80


4724
GLU
CG
30.693
66.725
37.585
47.61


4725
GLU
CD
29.211
66.293
37.462
55.88


4726
GLU
OE1
28.422
67.129
36.998
59.76


4727
GLU
OE2
28.883
65.134
37.826
61.03


4728
GLU
H
32.243
64.712
37.176
20.00


4729
GLU
HA
30.410
65.251
35.271
20.00


4730
GLU
1HB
31.181
67.661
35.698
20.00


4731
GLU
2HB
32.564
67.009
36.547
20.00


4732
GLU
1HG
30.708
67.672
38.117
20.00


4733
GLU
2HG
31.080
65.993
38.276
20.00


4734
LEU
N
33.317
65.813
33.793
24.19


4735
LEU
CA
34.088
66.004
32.540
23.43


4736
LEU
C
34.108
64.773
31.610
24.08


4737
LEU
O
34.441
64.885
30.447
22.85


4738
LEU
CB
35.553
66.277
32.956
25.02


4739
LEU
CG
35.989
67.725
32.878
25.39


4740
LEU
CD1
37.358
67.805
33.605
27.03


4741
LEU
CD2
34.947
68.615
33.583
28.40


4742
LEU
H
33.756
65.871
34.690
20.00


4743
LEU
HA
33.699
66.832
31.949
20.00


4744
LEU
1HB
36.274
65.707
32.372
20.00


4745
LEU
2HB
35.693
65.929
33.976
20.00


4746
LEU
HG
36.089
68.033
31.838
20.00


4747
LEU
1HD1
38.106
67.202
33.097
20.00


4748
LEU
2HD1
37.284
67.450
34.634
20.00


4749
LEU
3HD1
37.742
68.825
33.641
20.00


4750
LEU
1HD2
34.769
68.279
34.605
20.00


4751
LEU
2HD2
33.982
68.644
33.078
20.00


4752
LEU
3HD2
35.307
69.642
33.676
20.00


4753
SER
N
33.842
63.591
32.146
23.22


4754
SER
CA
34.023
62.430
31.279
24.53


4755
SER
C
32.729
62.144
30.475
26.87


4756
SER
O
32.753
61.539
29.414
26.47


4757
SER
CB
34.168
61.268
32.238
23.92


4758
SER
OG
32.851
60.942
32.814
27.33


4759
SER
H
33.548
63.568
33.105
20.00


4760
SER
HA
34.900
62.512
30.638
20.00


4761
SER
1HB
35.074
61.383
32.907
20.00


4762
SER
2HB
34.520
60.416
31.633
20.00


4763
SER
HG
32.219
61.568
33.301
20.00


4764
HIS
N
31.582
62.546
31.085
29.80


4765
HIS
CA
30.257
62.150
30.557
33.13


4766
HIS
O
29.778
60.651
30.861
33.64


4767
HIS
O
29.195
59.996
29.999
31.30


4768
HIS
CB
30.150
62.548
29.063
36.51


4769
HIS
CG
30.638
63.959
28.940
40.71


4770
HIS
ND1
31.746
64.287
28.246
43.97


4771
HIS
CD2
30.108
65.137
29.519
42.68


4772
HIS
CE1
31.894
65.632
28.386
43.60


4773
HIS
NE2
30.917
66.174
29.151
42.67


4774
HIS
H
31.682
63.199
31.841
20.00


4775
HIS
HA
29.569
62.773
31.127
20.00


4776
HIS
1HB
29.124
62.477
28.704
20.00


4777
HIS
2HB
30.767
61.968
28.391
20.00


4778
HIS
HD1
32.351
63.667
27.792
20.00


4779
HIS
HD2
29.244
65.194
30.166
20.00


4780
HIS
HE1
32.696
66.220
27.957
20.00


4781
GLU
N
30.038
60.148
32.122
35.19


4782
GLU
CA
29.812
58.725
32.461
36.70


4783
GLU
C
28.365
58.293
32.195
38.60


4784
GLU
O
28.187
57.171
31.764
37.53


4785
GLU
CB
30.385
58.171
33.820
35.82


4786
GLU
CG
29.685
58.624
35.121
36.20


4787
GLU
CD
30.185
57.959
36.421
38.96


4788
GLU
OE1
31.324
57.527
36.458
36.60


4789
GLU
OE2
29.434
57.837
37.399
41.14


4790
GLU
H
30.309
60.799
32.826
20.00


4791
GLU
HA
30.412
58.167
31.757
20.00


4792
GLU
1HB
31.453
58.377
33.892
20.00


4793
GLU
2HB
30.305
57.095
33.743
20.00


4794
GLU
1HG
28.617
58.448
35.059
20.00


4795
GLU
2HG
29.808
59.700
35.259
20.00


4796
ASP
N
27.355
59.161
32.427
42.63


4797
ASP
CA
25.947
58.715
32.232
46.40


4798
ASP
C
25.333
59.095
30.796
47.19


4799
ASP
O
25.663
60.179
30.242
46.38


4800
ASP
CB
25.156
59.121
33.508
50.98


4801
ASP
CG
25.757
58.386
34.723
57.85


4802
ASP
OD1
25.724
57.146
34.731
60.50


4803
ASP
OD2
26.292
59.021
35.648
61.02


4804
ASP
OXT
24.582
58.276
30.208
48.57


4805
ASP
H
27.519
60.002
32.926
20.00


4806
ASP
HA
25.950
57.622
32.219
20.00


4807
ASP
1HB
24.118
58.815
33.431
20.00


4808
ASP
2HB
25.188
60.198
33.649
20.00


1
OC—
C1
49.640
37.719
14.003
0.00


2
OC—
C2
50.787
38.141
14.736
0.00


3
OC—
C3
51.008
39.495
14.916
0.00


4
OC—
C4
50.154
40.364
14.322
0.00


5
OC—
C5
49.053
40.047
13.581
0.00


6
OC—
C6
48.782
38.701
13.402
0.00


7
OC—
7H
49.187
36.718
13.842
0.00


8
OC—
8H
48.426
40.820
13.123
0.00


9
OC—
H9
47.921
38.415
12.808
0.00


10
OC—
C10
52.036
40.299
15.636
0.00


11
OC—
N11
51.728
41.572
15.438
0.00


12
OC—
C12
50.628
41.640
14.622
0.00


13
OC—
O13
50.068
42.623
14.140
0.00


14
OC—
O14
52.998
39.925
16.291
0.00


15
OC—
O15
51.718
37.289
15.246
0.00


16
OC—
H16
51.994
36.801
14.488
0.00


17
OC—
C17
52.602
42.662
15.945
0.00


18
OC—
C18
51.989
43.758
16.830
0.00


19
OC—
H19
53.162
43.136
15.129
0.00


20
OC—
H20
53.441
42.237
16.493
0.00


21
OC—
O21
52.823
43.764
17.935
0.00


22
OC—
C22
52.911
44.965
18.630
0.00


23
OC—
C23
51.464
45.106
19.104
0.00


24
OC—
C24
50.401
44.489
18.575
0.00


25
OC—
C25
50.577
43.599
17.383
0.00


26
OC—
6H2
52.083
44.717
16.324
0.00


27
OC—
H27
53.299
45.778
18.011
0.00


28
OC—
H28
53.618
44.846
19.458
0.00


29
OC—
9H2
49.817
43.779
16.639
0.00


30
OC—
0H3
50.512
42.573
17.745
0.00


31
OC—
S31
50.995
45.860
20.622
0.00


32
OC—
C32
49.309
45.615
20.276
0.00


33
OC—
C33
49.082
44.948
19.126
0.00


34
OC—
N34
48.236
46.161
21.034
0.00


35
OC—
C35
48.405
46.833
22.220
0.00


36
OC—
C36
47.021
47.267
22.889
0.00


37
OC—
O37
46.749
48.354
23.338
0.00


38
OC—
O38
46.116
46.291
23.042
0.00


39
OC—
O39
49.477
47.023
22.820
0.00


40
OC—
C40
47.697
44.874
18.500
0.00


41
OC—
O41
46.650
44.969
19.070
0.00


42
OC—
O42
47.614
44.562
17.174
0.00


43
OC—
3H4
46.996
43.859
17.092
0.00


44
OC—
H44
45.261
46.650
23.184
0.00


45
OC—
H45
47.336
46.168
20.596
0.00


1
TIP
OH2
55.419
44.829
16.389
20.00


2
TIP
H1
55.536
44.889
17.342
20.00


3
TIP
2H
55.300
45.765
16.164
20.00


4
TIP
OH2
50.936
38.099
22.176
20.00


5
TIP
1H
51.119
38.023
23.113
20.00


6
TIP
H2
50.913
39.042
22.012
20.00


7
TIP
OH2
29.774
30.704
38.242
20.00


8
TIP
1H
29.956
30.628
39.179
20.00


9
TIP
H2
29.750
31.647
38.078
20.00


10
TIP
OH2
45.277
35.890
28.823
20.00


11
TIP
1H
45.460
35.813
29.759
20.00


12
TIP
H2
45.253
36.832
28.659
20.00


13
TIP
OH2
58.027
40.785
28.285
20.00


14
TIP
1H
58.210
40.709
29.222
20.00


15
TIP
H2
58.004
41.728
28.121
20.00


16
TIP
OH2
40.267
36.083
19.326
20.00


17
TIP
H1
40.450
36.007
20.263
20.00


18
TIP
2H
40.244
37.026
19.162
20.00


19
TIP
OH2
53.647
32.258
38.649
20.00


20
TIP
1H
53.830
32.182
39.585
20.00


21
TIP
H2
53.623
33.200
38.484
20.00


22
TIP
OH2
48.317
32.381
26.654
20.00


23
TIP
1H
48.499
32.305
27.591
20.00


24
TIP
H2
48.293
33.324
26.490
20.00


25
TIP
OH2
38.532
50.364
24.358
20.00


26
TIP
1H
38.714
50.288
25.294
20.00


27
TIP
H2
38.508
51.307
24.194
20.00


28
TIP
OH2
43.205
42.135
42.424
20.00


29
TIP
1H
43.387
42.059
43.360
20.00


30
TIP
2H
43.181
43.078
42.260
20.00


31
TIP
OH2
38.345
49.997
21.607
20.00


32
TIP
H1
38.528
49.921
22.543
20.00


33
TIP
H2
38.321
50.940
21.443
20.00


34
TIP
OH2
48.352
30.997
37.771
20.00


35
TIP
1H
48.535
30.921
38.708
20.00


36
TIP
H2
48.329
31.940
37.607
20.00


37
TIP
OH2
48.526
24.351
23.768
20.00


38
TIP
H1
48.709
24.275
24.705
20.00


39
TIP
2H
48.502
25.294
23.604
20.00


40
TIP
OH2
30.895
32.557
49.007
20.00


41
TIP
H1
31.078
32.480
49.944
20.00


42
TIP
2H
30.871
33.499
48.843
20.00


43
TIP
OH2
48.519
50.061
21.813
20.00


44
TIP
H1
48.702
49.985
22.750
20.00


45
TIP
2H
48.495
51.003
21.649
20.00


46
TIP
OH2
57.848
51.344
42.042
20.00


47
TIP
H1
58.031
51.268
42.978
20.00


48
TIP
2H
57.825
52.287
41.877
20.00


49
TIP
OH2
54.834
35.583
21.192
20.00


50
TIP
1H
55.017
35.507
22.129
20.00


51
TIP
H2
54.811
36.525
21.028
20.00


52
TIP
OH2
21.604
40.670
37.071
20.00


53
TIP
H1
21.787
40.594
38.007
20.00


54
TIP
2H
21.581
41.613
36.907
20.00


55
TIP
OH2
61.252
32.808
37.483
20.00


56
TIP
H1
61.435
32.732
38.420
20.00


57
TIP
2H
61.229
33.751
37.319
20.00


58
TIP
OH2
66.912
49.122
40.151
20.00


59
TIP
H1
67.094
49.046
41.088
20.00


60
TIP
2H
66.888
50.065
39.987
20.00


61
TIP
OH2
23.155
25.413
25.818
20.00


62
TIP
H1
23.337
25.337
26.755
20.00


63
TIP
2H
23.131
26.355
25.654
20.00


64
TIP
OH2
52.477
58.511
18.314
20.00


65
TIP
H1
52.659
58.434
19.250
20.00


66
TIP
2H
52.453
59.453
18.150
20.00


67
TIP
OH2
33.877
44.186
23.766
20.00


68
TIP
1H
34.060
44.110
24.702
20.00


69
TIP
H2
33.853
45.129
23.602
20.00


70
TIP
OH2
36.071
53.377
48.280
20.00


71
TIP
H1
36.254
53.301
49.216
20.00


72
TIP
2H
36.047
54.320
48.116
20.00


73
TIP
OH2
57.951
22.393
22.291
20.00


74
TIP
1H
58.133
22.317
23.228
20.00


75
TIP
H2
57.927
23.335
22.127
20.00


76
TIP
OH2
43.946
30.374
44.700
20.00


77
TIP
1H
44.128
30.298
45.637
20.00


78
TIP
H2
43.922
31.316
44.536
20.00


79
TIP
OH2
23.284
48.767
33.067
20.00


80
TIP
1H
23.466
48.691
34.004
20.00


81
TIP
H2
23.260
49.710
32.903
20.00


82
TIP
OH2
34.465
36.411
46.836
20.00


83
TIP
1H
34.648
36.335
47.773
20.00


84
TIP
H2
34.441
37.353
46.672
20.00


85
TIP
OH2
47.183
59.524
19.471
20.00


86
TIP
H1
47.365
59.448
20.407
20.00


87
TIP
2H
47.159
60.467
19.307
20.00


88
TIP
OH2
38.194
26.639
27.880
20.00


89
TIP
1H
38.377
26.563
28.816
20.00


90
TIP
H2
38.170
27.581
27.716
20.00


91
TIP
OH2
63.749
46.405
40.207
20.00


92
TIP
1H
63.932
46.329
41.143
20.00


93
TIP
H2
63.726
47.347
40.043
20.00


94
TIP
OH2
38.952
29.220
51.044
20.00


95
TIP
1H
39.135
29.144
51.980
20.00


96
TIP
H2
38.928
30.162
50.880
20.00


97
TIP
OH2
22.585
40.880
29.562
20.00


98
TIP
H1
22.768
40.804
30.498
20.00


99
TIP
2H
22.562
41.823
29.398
20.00


100
TIP
OH2
60.690
27.339
33.408
20.00


101
TIP
1H
60.873
27.263
34.345
20.00


102
TIP
H2
60.666
28.282
33.244
20.00


103
TIP
OH2
44.387
24.820
39.848
20.00


104
TIP
H1
44.570
24.744
40.784
20.00


105
TIP
H2
44.363
25.763
39.684
20.00


106
TIP
OH2
47.685
57.349
44.874
20.00


107
TIP
1H
47.867
57.272
45.810
20.00


108
TIP
H2
47.661
58.291
44.710
20.00


109
TIP
OH2
67.071
45.345
34.784
20.00


110
TIP
H1
67.254
45.268
35.720
20.00


111
TIP
2H
67.047
46.287
34.620
20.00


112
TIP
OH2
45.116
59.190
18.168
20.00


113
TIP
H1
45.298
59.114
19.105
20.00


114
TIP
2H
45.092
60.133
18.004
20.00


115
TIP
OH2
60.283
64.299
18.011
20.00


116
TIP
H1
60.466
64.223
18.947
20.00


117
TIP
2H
60.259
65.241
17.847
20.00


118
TIP
OH2
60.415
30.584
33.261
20.00


119
TIP
H1
60.598
30.508
34.198
20.00


120
TIP
2H
60.392
31.527
33.097
20.00


121
TIP
OH2
60.024
47.287
40.698
20.00


122
TIP
1H
60.207
47.211
41.634
20.00


123
TIP
H2
60.001
48.230
40.534
20.00


124
TIP
OH2
37.196
38.650
46.459
20.00


125
TIP
H1
37.379
38.574
47.395
20.00


126
TIP
2H
37.172
39.592
46.294
20.00


127
TIP
OH2
46.215
64.400
22.087
20.00


128
TIP
H1
46.398
64.324
23.024
20.00


129
TIP
2H
46.191
65.343
21.923
20.00


130
TIP
OH2
32.296
42.095
24.175
20.00


131
TIP
H1
32.479
42.019
25.112
20.00


132
TIP
2H
32.272
43.038
24.011
20.00


133
TIP
OH2
25.133
25.020
39.586
20.00


134
TIP
1H
25.316
24.944
40.523
20.00


135
TIP
2H
25.109
25.962
39.422
20.00


136
TIP
OH2
63.940
65.238
29.552
20.00


137
TIP
1H
64.123
65.162
30.489
20.00


138
TIP
H2
63.917
66.181
29.388
20.00


139
TIP
OH2
42.953
24.320
36.755
20.00


140
TIP
H1
43.135
24.244
37.692
20.00


141
TIP
2H
42.929
25.263
36.591
20.00


142
TIP
OH2
31.728
20.196
39.928
20.00


143
TIP
1H
31.910
20.120
40.864
20.00


144
TIP
H2
31.704
21.139
39.764
20.00


145
TIP
OH2
63.074
44.498
42.664
20.00


146
TIP
H1
63.256
44.422
43.600
20.00


147
TIP
H2
63.050
45.441
42.500
20.00


148
TIP
OH2
57.929
49.570
22.490
20.00


149
TIP
1H
58.112
49.494
23.426
20.00


150
TIP
2H
57.906
50.513
22.325
20.00


151
TIP
OH2
37.261
57.330
21.133
20.00


152
TIP
1H
37.444
57.254
22.070
20.00


153
TIP
2H
37.238
58.273
20.969
20.00


154
TIP
OH2
49.491
44.986
44.949
20.00


155
TIP
H1
49.673
44.910
45.886
20.00


156
TIP
2H
49.467
45.929
44.785
20.00


157
TIP
OH2
58.235
25.415
34.562
20.00


158
TIP
1H
58.417
25.339
35.498
20.00


159
TIP
H2
58.211
26.358
34.398
20.00


160
TIP
OH2
39.581
24.265
39.192
20.00


161
TIP
H1
39.763
24.189
40.129
20.00


162
TIP
2H
39.557
25.208
39.028
20.00


163
TIP
OH2
26.644
29.865
39.722
20.00


164
TIP
H1
26.827
29.789
40.658
20.00


165
TIP
2H
26.620
30.807
39.558
20.00


166
TIP
OH2
46.323
43.759
44.595
20.00


167
TIP
H1
46.506
43.683
45.532
20.00


168
TIP
2H
46.300
44.701
44.431
20.00
















TABLE D







Table of the orthogonal three dimensional coordinates in Ångstroms and


B factors (Å2) for Protein Tyrosine Phosphatase 1B complexed with


2-(oxalyl-amino)-7-(1,1,3-trioxo-1H-benzo[d]isothiazol-3-yloxomethyl)-


4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid and the water


molecule which forms hydrogen bonds with the pyran oxygen atom, the


side chain oxygen atom and aspartic acid 48 (Example XX).












No
Amino acid
X
Y
Z
B
















1
GLU
N
21.703
70.016
37.889
44.68


2
GLU
CA
20.473
69.206
37.782
43.88


3
GLU
C
20.313
68.401
36.438
42.17


4
GLU
O
20.963
68.696
35.441
41.34


5
GLU
CB
19.333
70.227
37.986
46.14


6
GLU
CG
17.913
69.694
38.169
53.54


7
GLU
CD
17.723
68.479
39.088
61.73


8
GLU
OE1
16.693
68.363
39.735
64.31


9
GLU
OE2
18.581
67.618
39.170
63.66


10
MET
N
19.366
67.432
36.416
39.32


11
MET
CA
18.893
66.684
35.226
34.55


12
MET
C
18.088
67.589
34.297
32.30


13
MET
O
18.046
67.444
33.093
32.26


14
MET
CB
17.971
65.501
35.627
34.25


15
MET
CG
16.763
65.884
36.525
32.80


16
MET
SD
15.642
64.525
36.918
29.12


17
MET
CE
16.780
63.485
37.833
28.64


18
GLU
N
17.444
68.545
34.943
32.02


19
GLU
CA
16.660
69.568
34.282
35.48


20
GLU
C
17.565
70.545
33.478
34.80


21
GLU
O
17.324
70.861
32.328
34.07


22
GLU
CB
15.843
70.226
35.377
37.66


23
GLU
CG
14.638
71.016
34.859
41.16


24
GLU
CD
13.640
71.228
36.010
44.68


25
GLU
OE1
14.018
71.066
37.168
43.98


26
GLU
OE2
12.488
71.540
35.734
47.38


27
LYS
N
18.704
70.909
34.098
35.30


28
LYS
CA
19.749
71.591
33.318
36.11


29
LYS
C
20.297
70.750
32.115
33.14


30
LYS
O
20.337
71.206
30.978
32.17


31
LYS
CB
20.887
72.023
34.258
40.81


32
LYS
CG
20.524
73.209
35.174
47.76


33
LYS
CD
21.621
73.495
36.226
53.62


34
LYS
CE
21.051
73.908
37.587
55.86


35
LYS
NZ
21.885
73.368
38.677
56.39


36
GLU
N
20.701
69.500
32.404
31.78


37
GLU
CA
21.112
68.597
31.321
30.77


38
GLU
C
20.053
68.489
30.194
30.69


39
GLU
O
20.353
68.592
29.020
29.85


40
GLU
CB
21.406
67.217
31.894
32.53


41
GLU
CG
21.384
66.134
30.814
37.49


42
GLU
CD
22.178
64.888
31.173
38.32


43
GLU
OE1
22.206
64.433
32.300
42.27


44
GLU
OE2
22.785
64.379
30.267
40.62


45
PHE
N
18.794
68.321
30.587
30.73


46
PHE
CA
17.727
68.276
29.603
32.45


47
PHE
C
17.750
69.480
28.642
34.85


48
PHE
O
17.904
69.288
27.453
33.64


49
PHE
CB
16.381
68.223
30.320
30.35


50
PHE
CG
15.294
67.870
29.350
26.13


51
PHE
CD1
15.021
66.538
29.085
25.00


52
PHE
CD2
14.582
68.860
28.688
22.62


53
PHE
CE1
14.068
66.173
28.147
24.45


54
PHE
CE2
13.636
68.508
27.740
23.14


55
PHE
CZ
13.391
67.166
27.459
23.15


56
GLU
N
17.650
70.698
29.207
38.88


57
GLU
CA
17.603
71.927
28.405
42.49


58
GLU
C
18.812
71.977
27.485
40.63


59
GLU
O
18.782
72.264
26.313
38.60


60
GLU
CB
17.758
73.128
29.336
48.61


61
GLU
CG
16.586
73.249
30.307
59.10


62
GLU
CD
15.360
73.806
29.606
67.27


63
GLU
OE1
15.504
74.386
28.522
72.82


64
GLU
OE2
14.274
73.680
30.153
69.58


65
GLN
N
19.926
71.681
28.084
38.72


66
GLN
CA
21.182
71.677
27.384
39.05


67
GLN
C
21.295
70.629
26.263
36.85


68
GLN
O
21.920
70.876
25.239
37.31


69
GLN
CB
22.160
71.459
28.488
43.39


70
GLN
CG
23.600
71.228
28.046
51.02


71
GLN
CD
24.424
70.842
29.287
57.42


72
GLN
OE1
25.562
70.436
29.224
62.88


73
GLN
NE2
23.787
70.955
30.441
59.65


74
ILE
N
20.644
69.479
26.488
33.52


75
ILE
CA
20.568
68.460
25.480
28.82


76
ILE
C
19.654
68.921
24.295
27.31


77
ILE
O
19.969
68.894
23.110
27.61


78
ILE
CB
20.239
67.069
25.944
27.67


79
ILE
CG1
21.327
66.546
26.867
25.62


80
ILE
CG2
20.110
66.093
24.775
24.46


81
ILE
CD1
20.897
65.251
27.523
28.44


82
ASP
N
18.496
69.346
24.737
27.29


83
ASP
CA
17.539
69.884
23.816
28.22


84
ASP
C
18.093
71.055
22.974
29.77


85
ASP
O
17.950
71.106
21.763
29.46


86
ASP
CB
16.329
70.307
24.644
26.78


87
ASP
CG
15.094
69.454
24.346
25.32


88
ASP
OD1
15.182
68.402
23.784
25.41


89
ASP
OD2
14.023
69.884
24.659
25.96


90
LYS
N
18.772
71.968
23.654
34.04


91
LYS
CA
19.284
73.163
23.027
38.17


92
LYS
C
20.201
72.782
21.859
38.28


93
LYS
O
20.020
73.189
20.713
41.49


94
LYS
CB
20.015
74.041
24.063
43.91


95
LYS
CG
19.071
74.819
25.012
52.90


96
LYS
CD
19.799
75.829
25.904
58.71


97
LYS
CE
18.834
76.499
26.900
60.27


98
LYS
NZ
19.587
77.453
27.717
61.96


99
SER
N
21.163
71.912
22.177
35.28


100
SER
CA
22.098
71.545
21.090
33.50


101
SER
C
21.511
70.377
20.261
33.89


102
SER
O
22.246
69.714
19.554
35.89


103
SER
CB
23.342
70.937
21.788
32.34


104
SER
OG
22.978
69.903
22.780
34.77


105
GLY
N
20.201
70.097
20.417
32.04


106
GLY
CA
19.593
68.985
19.695
31.04


107
GLY
C
20.362
67.670
19.728
31.12


108
GLY
O
20.378
66.986
18.724
34.31


109
SER
N
20.977
67.282
20.858
29.06


110
SER
CA
21.777
66.031
20.725
26.56


111
SER
C
21.199
64.762
21.398
25.00


112
SER
O
21.940
63.835
21.667
26.10


113
SER
CB
23.233
66.335
21.115
28.79


114
SER
OG
23.361
67.063
22.382
32.58


115
TRP
N
19.855
64.639
21.554
22.56


116
TRP
CA
19.293
63.388
22.093
19.31


117
TRP
C
19.786
62.100
21.381
18.55


118
TRP
O
20.083
61.102
22.013
20.55


119
TRP
CB
17.751
63.440
22.080
17.74


120
TRP
CG
17.247
64.345
23.180
17.53


121
TRP
CD1
16.779
65.654
23.022
14.15


122
TRP
CD2
17.312
64.085
24.605
16.03


123
TRP
NE1
16.593
66.177
24.251
16.66


124
TRP
CE2
16.887
65.268
25.251
17.66


125
TRP
CE3
17.675
63.004
25.350
11.39


126
TRP
CZ2
16.898
65.347
26.623
18.08


127
TRP
CZ3
17.676
63.059
26.745
10.09


128
TRP
CH2
17.279
64.235
27.383
15.36


129
ALA
N
19.871
62.143
20.056
17.72


130
ALA
CA
20.202
60.910
19.307
17.15


131
ALA
C
21.652
60.428
19.547
15.94


132
ALA
O
21.895
59.243
19.607
16.09


133
ALA
CB
20.042
61.212
17.815
15.04


134
ALA
N
22.583
61.369
19.645
15.86


135
ALA
CA
23.953
61.087
20.057
16.56


136
ALA
C
24.062
60.639
21.520
17.32


137
ALA
O
24.632
59.609
21.781
18.09


138
ALA
CB
24.761
62.357
19.906
14.93


139
ILE
N
23.417
61.377
22.433
17.87


140
ILE
CA
23.245
60.832
23.789
19.03


141
ILE
C
22.763
59.345
23.796
18.11


142
ILE
O
23.305
58.438
24.409
18.57


143
ILE
CB
22.216
61.696
24.560
21.02


144
ILE
CG1
22.665
63.159
24.647
20.66


145
ILE
CG2
22.012
61.186
25.992
20.04


146
ILE
CD1
24.097
63.283
25.120
18.89


147
TYR
N
21.674
59.132
23.082
16.17


148
TYR
CA
21.120
57.794
23.060
17.24


149
TYR
C
22.043
56.788
22.376
19.36


150
TYR
O
22.300
55.706
22.907
19.20


151
TYR
CB
19.754
57.851
22.383
15.19


152
TYR
CG
19.119
56.501
22.280
15.92


153
TYR
CD1
18.853
55.782
23.434
14.65


154
TYR
CD2
18.790
55.967
21.035
16.31


155
TYR
CE1
18.267
54.556
23.417
13.96


156
TYR
CE2
18.159
54.733
20.979
14.00


157
TYR
CZ
17.905
54.008
22.163
14.32


158
TYR
OH
17.345
52.759
21.944
11.00


159
GLN
N
22.561
57.160
21.194
21.20


160
GLN
CA
23.605
56.331
20.588
24.13


161
GLN
C
24.713
56.001
21.593
21.45


162
GLN
O
25.184
54.880
21.631
20.37


163
GLN
CB
24.248
56.982
19.353
34.41


164
GLN
CG
25.321
56.035
18.773
49.84


165
GLN
CD
26.136
56.556
17.565
62.54


166
GLN
OE1
26.977
55.883
16.989
66.64


167
GLN
NE2
25.813
57.794
17.172
67.57


168
ASP
N
25.085
57.002
22.391
21.19


169
ASP
CA
26.174
56.832
23.339
23.68


170
ASP
C
25.858
55.716
24.328
23.38


171
ASP
O
26.600
54.749
24.489
24.87


172
ASP
CB
26.451
58.140
24.079
28.19


173
ASP
CG
27.103
59.205
23.199
31.40


174
ASP
OD1
27.483
58.905
22.061
34.52


175
ASP
OD2
27.221
60.349
23.646
34.31


176
ILE
N
24.627
55.828
24.873
21.79


177
ILE
CA
24.154
54.745
25.716
20.54


178
ILE
C
24.220
53.381
24.999
20.53


179
ILE
O
24.664
52.384
25.562
19.96


180
ILE
CB
22.722
55.057
26.188
19.90


181
ILE
CG1
22.746
56.121
27.295
18.92


182
ILE
CG2
22.002
53.809
26.709
13.13


183
ILE
CD1
21.427
56.904
27.348
23.15


184
ARG
N
23.711
53.345
23.741
20.41


185
ARG
CA
23.715
52.099
22.985
22.09


186
ARG
C
25.141
51.469
22.930
23.43


187
ARG
O
25.286
50.258
23.023
21.33


188
ARG
CB
23.088
52.300
21.584
24.59


189
ARG
CG
21.532
52.302
21.526
27.48


190
ARG
CD
20.912
52.327
20.101
32.84


191
ARG
NE
19.450
52.168
20.157
43.35


192
ARG
CZ
18.645
51.724
19.167
44.57


193
ARG
NH1
19.112
51.575
17.953
46.24


194
ARG
NH2
17.395
51.443
19.393
38.15


195
HIS
N
26.156
52.353
22.819
26.24


196
HIS
CA
27.538
51.876
22.706
29.54


197
HIS
C
28.137
51.358
24.001
30.14


198
HIS
O
28.822
50.348
24.027
31.41


199
HIS
CB
28.432
52.975
22.150
35.11


200
HIS
CG
28.242
52.899
20.676
45.77


201
HIS
ND1
28.436
51.769
19.968
50.82


202
HIS
CD2
27.726
53.883
19.830
48.72


203
HIS
CE1
28.026
52.047
18.726
53.20


204
HIS
NE2
27.594
53.318
18.613
51.96


205
GLU
N
27.850
52.116
25.059
29.74


206
GLU
CA
28.217
51.750
26.423
26.86


207
GLU
C
27.461
50.503
26.956
25.10


208
GLU
O
27.958
49.784
27.824
25.66


209
GLU
CB
27.885
52.987
27.258
29.73


210
GLU
CG
28.749
54.190
26.816
36.62


211
GLU
CD
28.227
55.576
27.238
42.17


212
GLU
OE1
27.415
55.678
28.155
43.56


213
GLU
OE2
28.663
56.549
26.634
42.82


214
ALA
N
26.224
50.276
26.460
22.66


215
ALA
CA
25.424
49.170
27.037
19.17


216
ALA
C
26.192
47.808
27.064
17.78


217
ALA
O
27.027
47.515
26.229
18.91


218
ALA
CB
24.115
49.032
26.262
11.88


219
SER
N
25.866
47.002
28.076
16.59


220
SER
CA
26.466
45.670
28.261
15.02


221
SER
C
26.067
44.661
27.239
15.21


222
SER
O
25.057
44.724
26.572
14.30


223
SER
CB
25.928
45.219
29.658
13.45


224
SER
OG
26.076
46.179
30.730
20.52


225
ASP
N
26.914
43.640
27.200
18.46


226
ASP
CA
26.637
42.515
26.346
18.64


227
ASP
C
27.079
41.224
27.054
16.04


228
ASP
O
28.233
41.010
27.385
17.44


229
ASP
CB
27.372
42.760
25.036
23.76


230
ASP
CG
26.832
41.802
23.989
28.93


231
ASP
OD1
25.701
41.295
24.133
29.41


232
ASP
OD2
27.537
41.564
23.023
33.21


233
PHE
N
26.075
40.401
27.320
14.88


234
PHE
CA
26.312
39.115
27.938
12.14


235
PHE
C
25.696
37.991
27.085
10.36


236
PHE
O
24.778
38.182
26.301
14.29


237
PHE
CB
25.708
39.121
29.344
9.41


238
PHE
CG
26.277
40.180
30.227
10.05


239
PHE
CD1
27.508
39.992
30.862
12.58


240
PHE
CD2
25.566
41.344
30.471
6.85


241
PHE
CE1
28.002
40.930
31.768
9.43


242
PHE
CE2
26.045
42.265
31.390
5.14


243
PHE
CZ
27.251
42.063
32.036
7.18


244
PRO
N
26.241
36.762
27.253
7.14


245
PRO
CA
25.755
35.675
26.473
6.52


246
PRO
C
24.277
35.394
26.679
9.69


247
PRO
O
23.748
35.569
27.762
12.15


248
PRO
CB
26.607
34.503
26.897
3.58


249
PRO
CG
27.467
34.928
28.059
4.26


250
PRO
CD
27.366
36.422
28.133
3.15


251
CYS
N
23.626
34.982
25.597
12.69


252
CYS
CA
22.261
34.498
25.720
14.65


253
CYS
C
22.172
33.102
25.112
17.19


254
CYS
O
21.342
32.783
24.256
16.47


255
CYS
CB
21.300
35.454
25.016
13.35


256
CYS
SG
21.382
37.237
25.396
15.48


257
ARG
N
23.129
32.258
25.541
18.46


258
ARG
CA
23.174
30.921
24.986
19.34


259
ARG
C
21.865
30.155
25.153
19.02


260
ARG
O
21.360
29.596
24.201
20.59


261
ARG
CB
24.339
30.190
25.590
24.24


262
ARG
CG
25.684
30.614
24.976
34.28


263
ARG
CD
26.506
31.531
25.846
42.36


264
ARG
NE
26.067
31.510
27.243
47.65


265
ARG
CZ
26.832
31.598
28.306
47.20


266
ARG
NH1
28.125
31.583
28.117
46.56


267
ARG
NH2
26.311
31.717
29.498
44.55


268
VAL
N
21.246
30.117
26.340
17.94


269
VAL
CA
20.046
29.252
26.364
16.39


270
VAL
C
18.870
29.732
25.445
16.62


271
VAL
O
18.228
28.961
24.769
20.22


272
VAL
CB
19.708
28.709
27.746
14.40


273
VAL
CG1
18.301
29.008
28.203
13.66


274
VAL
CG2
20.727
29.076
28.805
11.01


275
ALA
N
18.666
31.040
25.380
16.61


276
ALA
CA
17.795
31.721
24.438
13.61


277
ALA
C
18.036
31.352
23.035
12.12


278
ALA
O
17.160
31.403
22.187
12.55


279
ALA
CB
18.080
33.255
24.451
10.37


280
LYS
N
19.303
31.043
22.828
11.81


281
LYS
CA
19.667
30.701
21.490
12.07


282
LYS
C
19.712
29.217
21.190
13.74


283
LYS
O
19.996
28.858
20.061
17.30


284
LYS
CB
20.968
31.391
21.154
12.40


285
LYS
CG
20.822
32.884
20.934
13.01


286
LYS
CD
19.574
33.099
20.085
17.78


287
LYS
CE
19.498
34.385
19.324
22.14


288
LYS
NZ
18.143
34.532
18.753
25.46


289
LEU
N
19.358
28.374
22.149
13.01


290
LEU
CA
19.324
26.958
21.822
13.50


291
LEU
C
18.159
26.587
20.853
16.14


292
LEU
O
17.057
27.133
20.907
14.24


293
LEU
CB
19.105
26.163
23.118
11.77


294
LEU
CG
20.222
26.230
24.139
8.45


295
LEU
CD1
21.462
25.514
23.666
2.00


296
LEU
CD2
19.752
25.632
25.474
5.67


297
PRO
N
18.411
25.594
19.966
18.99


298
PRO
CA
17.420
25.201
18.974
20.81


299
PRO
C
16.038
24.817
19.486
21.23


300
PRO
O
15.028
25.094
18.853
23.12


301
PRO
CB
18.053
23.970
18.312
22.01


302
PRO
CG
19.544
24.226
18.419
20.31


303
PRO
CD
19.693
24.935
19.760
21.95


304
LYS
N
16.032
24.245
20.703
20.72


305
LYS
CA
14.730
23.878
21.253
20.41


306
LYS
C
13.860
25.101
21.665
22.87


307
LYS
O
12.648
25.010
21.812
25.57


308
LYS
CB
14.945
22.949
22.437
19.35


309
LYS
CG
15.755
23.579
23.575
18.95


310
LYS
CD
15.710
22.689
24.822
21.88


311
LYS
CE
16.801
23.034
25.823
28.88


312
LYS
NZ
16.535
22.399
27.128
34.05


313
ASN
N
14.556
26.233
21.841
20.66


314
ASN
CA
13.870
27.431
22.279
18.39


315
ASN
C
13.486
28.352
21.122
18.29


316
ASN
O
12.970
29.444
21.354
16.34


317
ASN
CB
14.739
28.164
23.298
16.54


318
ASN
CG
14.821
27.389
24.621
18.02


319
ASN
OD1
13.969
26.599
24.993
18.28


320
ASN
ND2
15.875
27.678
25.307
15.54


321
LYS
N
13.754
27.923
19.857
19.25


322
LYS
CA
13.464
28.846
18.745
20.87


323
LYS
C
12.043
29.452
18.860
18.97


324
LYS
O
11.823
30.654
18.781
18.79


325
LYS
CB
13.693
28.184
17.377
25.70


326
LYS
CG
14.211
29.179
16.316
33.55


327
LYS
CD
14.555
28.542
14.949
41.05


328
LYS
CE
15.066
29.579
13.926
44.78


329
LYS
NZ
14.971
29.087
12.537
44.25


330
ASN
N
11.091
28.544
19.113
15.61


331
ASN
CA
9.708
28.969
19.134
14.25


332
ASN
C
9.210
29.512
20.495
13.55


333
ASN
O
8.012
29.666
20.711
11.55


334
ASN
CB
8.855
27.796
18.681
14.58


335
ASN
CG
8.704
26.756
19.791
18.11


336
ASN
OD1
9.204
26.857
20.899
19.64


337
ASN
ND2
7.912
25.772
19.462
22.97


338
ARG
N
10.163
29.703
21.400
12.38


339
ARG
CA
9.830
30.375
22.640
12.69


340
ARG
C
10.255
31.846
22.554
11.47


341
ARG
O
10.045
32.608
23.480
10.92


342
ARG
CB
10.492
29.633
23.827
12.58


343
ARG
CG
9.840
28.263
24.143
7.25


344
ARG
CD
10.452
27.622
25.391
6.96


345
ARG
NE
9.754
26.378
25.717
10.56


346
ARG
CZ
9.591
25.939
26.964
12.63


347
ARG
NH1
10.049
26.621
27.978
13.70


348
ARG
NH2
8.970
24.830
27.205
13.18


349
ASN
N
10.877
32.231
21.416
11.45


350
ASN
CA
11.276
33.639
21.283
10.48


351
ASN
C
10.479
34.359
20.189
10.61


352
ASN
O
10.425
33.924
19.054
12.34


353
ASN
CB
12.749
33.695
20.923
9.53


354
ASN
CG
13.512
33.223
22.114
13.73


355
ASN
OD1
13.255
33.613
23.245
15.94


356
ASN
ND2
14.468
32.378
21.802
13.53


357
ARG
N
9.906
35.498
20.587
9.18


358
ARG
CA
9.132
36.240
19.605
7.77


359
ARG
C
9.980
36.947
18.540
6.85


360
ARG
O
9.628
37.017
17.379
6.50


361
ARG
CB
8.232
37.214
20.383
7.45


362
ARG
CG
7.408
38.017
19.428
5.78


363
ARG
CD
6.595
39.001
20.150
7.80


364
ARG
NE
5.520
38.392
20.894
7.84


365
ARG
CZ
4.356
38.086
20.319
6.71


366
ARG
NH1
4.093
38.311
19.075
3.66


367
ARG
NH2
3.466
37.541
21.012
3.47


368
TYR
N
11.110
37.522
18.982
8.09


369
TYR
CA
11.994
38.167
18.021
7.20


370
TYR
C
13.398
37.575
18.097
10.87


371
TYR
O
13.994
37.455
19.164
11.24


372
TYR
CB
12.115
39.628
18.386
5.76


373
TYR
CG
10.820
40.320
18.388
7.25


374
TYR
CD1
10.123
40.388
17.212
10.32


375
TYR
CD2
10.304
40.862
19.541
3.38


376
TYR
CE1
8.881
40.994
17.151
12.06


377
TYR
CE2
9.097
41.526
19.474
8.53


378
TYR
CZ
8.354
41.606
18.291
12.52


379
TYR
OH
7.116
42.223
18.267
12.22


380
ARG
N
13.917
37.304
16.886
12.71


381
ARG
CA
15.268
36.791
16.740
14.19


382
ARG
C
16.325
37.589
17.518
15.21


383
ARG
O
17.239
36.987
18.070
17.69


384
ARG
CB
15.618
36.796
15.242
16.20


385
ARG
CG
16.894
36.009
14.934
20.90


386
ARG
CD
17.513
36.381
13.600
24.13


387
ARG
NE
18.032
37.734
13.679
31.45


388
ARG
CZ
18.180
38.440
12.559
35.35


389
ARG
NH1
18.031
37.849
11.400
34.27


390
ARG
NH2
18.426
39.722
12.626
36.59


391
ASP
N
16.129
38.922
17.483
15.52


392
ASP
CA
17.068
39.945
17.947
14.40


393
ASP
C
16.939
40.307
19.430
12.23


394
ASP
O
17.780
41.001
19.966
11.34


395
ASP
CB
16.825
41.235
17.144
19.70


396
ASP
CG
17.502
41.193
15.756
24.49


397
ASP
OD1
18.205
40.237
15.418
27.69


398
ASP
OD2
17.350
42.135
14.999
25.18


399
VAL
N
15.836
39.831
20.061
13.80


400
VAL
CA
15.628
40.144
21.478
13.65


401
VAL
C
15.556
38.911
22.396
13.05


402
VAL
O
14.676
38.066
22.356
10.76


403
VAL
CB
14.512
41.187
21.704
14.37


404
VAL
CG1
13.751
41.144
23.012
10.38


405
VAL
CG2
13.935
41.930
20.498
12.19


406
SER
N
16.585
38.852
23.257
14.06


407
SER
CA
16.846
37.705
24.127
9.73


408
SER
C
17.249
38.159
25.487
8.28


409
SER
O
17.770
39.230
25.677
5.98


410
SER
CB
17.993
36.869
23.463
10.62


411
SER
OG
17.811
36.472
22.071
11.36


412
PRO
N
16.972
37.263
26.461
7.35


413
PRO
CA
17.450
37.352
27.792
8.44


414
PRO
C
18.908
36.905
27.921
11.00


415
PRO
O
19.259
35.821
27.503
13.36


416
PRO
CB
16.474
36.351
28.513
7.21


417
PRO
CG
16.182
35.277
27.531
11.53


418
PRO
CD
16.259
36.046
26.224
9.12


419
PHE
N
19.753
37.763
28.507
10.36


420
PHE
CA
21.035
37.197
28.928
8.56


421
PHE
C
20.847
35.981
29.853
10.75


422
PHE
O
19.894
35.899
30.634
12.42


423
PHE
CB
21.829
38.225
29.725
6.92


424
PHE
CG
21.969
39.566
29.090
4.90


425
PHE
CD1
22.372
39.651
27.773
2.00


426
PHE
CD2
21.749
40.718
29.841
3.60


427
PHE
CE1
22.581
40.893
27.214
3.30


428
PHE
CE2
21.964
41.964
29.276
2.19


429
PHE
CZ
22.390
42.047
27.962
2.00


430
ASP
N
21.804
35.056
29.764
11.92


431
ASP
CA
21.710
33.883
30.620
12.44


432
ASP
C
21.749
34.248
32.129
10.45


433
ASP
O
21.055
33.664
32.955
14.63


434
ASP
CB
22.852
32.934
30.260
13.15


435
ASP
CG
22.759
32.466
28.829
17.42


436
ASP
OD1
21.740
31.969
28.404
17.02


437
ASP
OD2
23.745
32.592
28.162
18.42


438
HIS
N
22.577
35.242
32.485
6.99


439
HIS
CA
22.781
35.415
33.933
7.65


440
HIS
C
21.522
35.922
34.692
11.47


441
HIS
O
21.329
35.728
35.891
12.59


442
HIS
CB
23.994
36.314
34.157
4.46


443
HIS
CG
23.699
37.794
34.137
5.10


444
HIS
ND1
23.259
38.489
35.219
8.84


445
HIS
CD2
23.892
38.696
33.091
5.96


446
HIS
CE1
23.198
39.775
34.852
5.13


447
HIS
NE2
23.568
39.921
33.577
7.85


448
SER
N
20.686
36.648
33.929
11.96


449
SER
CA
19.591
37.347
34.601
10.61


450
SER
C
18.221
36.722
34.179
11.50


451
SER
O
17.161
37.166
34.622
13.21


452
SER
CB
19.578
38.795
34.005
6.54


453
SER
OG
19.426
38.747
32.546
11.00


454
ARG
N
18.259
35.718
33.274
10.94


455
ARG
CA
16.999
35.170
32.768
12.70


456
ARG
C
16.139
34.506
33.898
14.39


457
ARG
O
16.647
33.926
34.844
12.31


458
ARG
CB
17.292
34.168
31.637
12.58


459
ARG
CG
17.894
32.846
32.135
14.19


460
ARG
CD
18.073
31.815
31.023
15.27


461
ARG
NE
18.531
30.520
31.560
15.37


462
ARG
CZ
17.720
29.463
31.683
15.74


463
ARG
NH1
16.468
29.566
31.330
13.61


464
ARG
NH2
18.150
28.339
32.167
13.65


465
ILE
N
14.811
34.584
33.745
16.19


466
ILE
CA
13.964
33.837
34.671
13.97


467
ILE
C
13.863
32.356
34.253
13.70


468
ILE
O
13.599
32.046
33.119
15.22


469
ILE
CB
12.583
34.496
34.725
14.29


470
ILE
CG1
12.697
35.981
35.109
14.68


471
ILE
CG2
11.695
33.761
35.745
14.23


472
ILE
CD1
12.768
36.193
36.625
11.53


473
LYS
N
14.079
31.452
35.184
15.41


474
LYS
CA
13.901
30.039
34.865
16.79


475
LYS
C
12.555
29.531
35.391
17.35


476
LYS
O
12.222
29.772
36.539
19.31


477
LYS
CB
14.952
29.273
35.664
17.97


478
LYS
CG
16.348
29.641
35.224
20.00


479
LYS
CD
17.342
28.756
35.923
21.07


480
LYS
CE
18.757
29.183
35.586
25.86


481
LYS
NZ
19.661
28.132
36.065
29.41


482
LEU
N
11.827
28.807
34.546
17.14


483
LEU
CA
10.659
28.096
35.026
16.17


484
LEU
C
11.101
26.982
35.997
18.46


485
LEU
O
12.139
26.361
35.815
16.31


486
LEU
CB
9.925
27.512
33.820
16.73


487
LEU
CG
9.241
28.474
32.838
16.01


488
LEU
CD1
9.233
28.140
31.340
18.22


489
LEU
CD2
9.174
29.942
33.208
19.99


490
HIS
N
10.307
26.720
37.031
20.86


491
HIS
CA
10.504
25.539
37.856
22.12


492
HIS
C
9.967
24.256
37.160
26.50


493
HIS
O
9.214
23.488
37.729
29.06


494
HIS
CB
9.795
25.710
39.208
20.80


495
HIS
CG
10.244
26.940
39.961
18.49


496
HIS
ND1
9.650
27.355
41.096
18.74


497
HIS
CD2
11.279
27.836
39.657
17.16


498
HIS
CE1
10.306
28.462
41.471
16.79


499
HIS
NE2
11.293
28.776
40.626
15.80


500
GLN
N
10.416
24.000
35.928
31.86


501
GLN
CA
9.989
22.769
35.260
36.18


502
GLN
C
11.226
22.046
34.724
37.67


503
GLN
O
12.153
22.676
34.251
38.03


504
GLN
CB
8.969
23.068
34.141
38.37


505
GLN
CG
9.413
24.118
33.110
45.32


506
GLN
CD
8.538
24.115
31.844
51.67


507
GLN
OE1
8.913
23.628
30.781
53.74


508
GLN
NE2
7.325
24.611
32.016
51.04


509
GLU
N
11.195
20.711
34.825
40.34


510
GLU
CA
12.374
19.917
34.434
41.41


511
GLU
C
12.545
19.806
32.896
40.03


512
GLU
O
13.654
19.763
32.381
38.15


513
GLU
CB
12.223
18.535
35.054
45.95


514
GLU
CG
12.189
18.568
36.590
52.82


515
GLU
CD
11.488
17.315
37.138
60.20


516
GLU
OE1
11.234
16.382
36.370
63.99


517
GLU
OE2
11.181
17.291
38.322
61.75


518
ASP
N
11.382
19.779
32.207
39.83


519
ASP
CA
11.403
19.725
30.735
37.84


520
ASP
C
12.238
20.863
30.075
31.75


521
ASP
O
13.278
20.692
29.439
32.35


522
ASP
CB
9.941
19.774
30.258
45.12


523
ASP
CG
9.937
19.953
28.726
53.29


524
ASP
OD1
10.589
19.165
28.040
57.18


525
ASP
OD2
9.363
20.939
28.246
56.58


526
ASN
N
11.695
22.072
30.254
26.65


527
ASN
CA
12.390
23.201
29.678
21.86


528
ASN
C
12.099
24.449
30.528
20.05


529
ASN
O
11.018
25.025
30.494
21.82


530
ASN
CB
11.951
23.347
28.213
18.23


531
ASN
CG
12.778
24.425
27.560
15.37


532
ASN
OD1
13.328
25.282
28.216
19.18


533
ASN
ND2
12.889
24.375
26.266
5.53


534
ASP
N
13.138
24.890
31.233
17.24


535
ASP
CA
12.969
26.055
32.084
15.50


536
ASP
C
12.983
27.419
31.339
13.37


537
ASP
O
12.998
28.461
31.970
16.65


538
ASP
CB
14.049
26.012
33.173
19.65


539
ASP
CG
15.459
26.514
32.718
24.75


540
ASP
OD1
15.644
27.054
31.628
25.78


541
ASP
OD2
16.425
26.355
33.444
27.00


542
TYR
N
13.057
27.417
29.999
11.69


543
TYR
CA
13.282
28.673
29.271
9.17


544
TYR
C
11.981
29.477
29.069
8.95


545
TYR
O
10.979
28.944
28.618
10.59


546
TYR
CB
14.044
28.417
27.937
9.39


547
TYR
CG
14.285
29.690
27.182
7.68


548
TYR
CD1
15.282
30.541
27.605
5.47


549
TYR
CD2
13.461
30.068
26.121
6.70


550
TYR
CE1
15.383
31.821
27.085
6.80


551
TYR
CE2
13.539
31.330
25.557
5.20


552
TYR
CZ
14.498
32.243
26.073
8.53


553
TYR
OH
14.596
33.555
25.625
8.14


554
ILE
N
12.050
30.770
29.393
8.87


555
ILE
CA
11.093
31.830
29.070
10.50


556
ILE
C
11.899
33.107
28.707
10.84


557
ILE
O
12.881
33.469
29.342
11.65


558
ILE
CB
10.060
32.108
30.209
11.32


559
ILE
CG1
9.000
33.151
29.783
10.88


560
ILE
CG2
10.719
32.543
31.525
10.89


561
ILE
CD1
7.704
33.146
30.591
8.77


562
ASN
N
11.470
33.812
27.665
8.42


563
ASN
CA
12.083
35.065
27.316
8.86


564
ASN
C
11.668
36.151
28.345
8.99


565
ASN
O
10.725
36.902
28.126
9.36


566
ASN
CB
11.679
35.428
25.878
7.09


567
ASN
CG
12.506
36.595
25.383
7.69


568
ASN
OD1
12.723
37.602
26.057
9.31


569
ASN
ND2
12.964
36.408
24.164
4.12


570
ALA
N
12.428
36.178
29.455
7.57


571
ALA
CA
12.160
37.033
30.608
8.59


572
ALA
C
13.456
37.271
31.452
9.69


573
ALA
O
14.277
36.377
31.571
9.38


574
ALA
CB
11.128
36.326
31.528
8.05


575
SER
N
13.603
38.481
32.012
8.59


576
SER
CA
14.773
38.835
32.876
9.14


577
SER
C
14.389
39.499
34.110
10.33


578
SER
O
13.476
40.308
34.125
12.06


579
SER
CB
15.574
39.938
32.054
7.95


580
SER
OG
15.690
39.635
30.644
8.20


581
LEU
N
15.179
39.173
35.149
9.68


582
LEU
CA
15.021
39.922
36.386
10.62


583
LEU
C
15.923
41.152
36.334
9.94


584
LEU
O
17.141
41.081
36.377
10.46


585
LEU
CB
15.343
38.989
37.549
10.83


586
LEU
CG
15.005
39.449
38.990
13.92


587
LEU
CD1
13.816
40.385
39.226
12.88


588
LEU
CD2
16.114
39.506
40.027
12.99


589
ILE
N
15.258
42.299
36.213
10.44


590
ILE
CA
15.971
43.551
36.356
10.17


591
ILE
C
16.048
43.883
37.879
13.89


592
ILE
O
15.070
44.274
38.505
15.18


593
ILE
GB
15.228
44.651
35.596
8.61


594
ILE
CG1
15.428
44.579
34.073
6.44


595
ILE
CG2
15.734
46.015
36.078
10.00


596
ILE
CD1
15.155
43.216
33.468
5.57


597
LYS
N
17.239
43.734
38.432
15.52


598
LYS
CA
17.380
43.928
39.856
15.20


599
LYS
C
18.176
45.182
40.221
15.99


600
LYS
O
19.398
45.244
40.138
15.65


601
LYS
CB
18.123
42.725
40.331
18.92


602
LYS
CG
18.087
42.602
41.836
24.92


603
LYS
CD
18.365
41.191
42.268
32.15


604
LYS
CE
17.900
40.926
43.679
39.12


605
LYS
NZ
18.225
39.537
44.018
44.57


606
MET
N
17.397
46.178
40.655
15.97


607
MET
CA
17.988
47.464
40.974
16.08


608
MET
C
18.400
47.544
42.462
17.49


609
MET
O
17.579
47.794
43.332
17.67


610
MET
CB
16.968
48.533
40.607
14.83


611
MET
CG
16.626
48.573
39.119
13.99


612
MET
SD
18.121
48.583
38.091
17.00


613
MET
CE
18.404
50.363
38.012
4.51


614
GLU
N
19.696
47.328
42.741
19.80


615
GLU
CA
20.201
47.101
44.094
21.74


616
GLU
C
20.060
48.353
44.993
21.70


617
GLU
O
19.551
48.311
46.106
21.22


618
GLU
CB
21.652
46.627
44.007
24.29


619
GLU
CG
22.273
46.291
45.379
31.56


620
GLU
CD
23.780
45.945
45.252
36.04


621
GLU
OE1
24.575
46.709
44.678
39.83


622
GLU
OE2
24.167
44.887
45.726
40.03


623
GLU
N
20.500
49.491
44.427
22.15


624
GLU
CA
20.486
50.733
45.200
22.50


625
GLU
C
19.056
51.237
45.483
22.61


626
GLU
O
18.690
51.633
46.586
23.83


627
GLU
CB
21.321
51.751
44.448
23.01


628
GLU
CG
21.465
53.095
45.163
29.10


629
GLU
CD
21.921
54.170
44.157
35.50


630
GLU
OE1
21.836
53.969
42.942
36.25


631
GLU
OE2
22.346
55.218
44.595
38.56


632
ALA
N
18.218
51.181
44.432
23.89


633
ALA
CA
16.788
51.506
44.582
21.87


634
ALA
C
16.051
50.494
45.447
20.77


635
ALA
O
15.078
50.857
46.077
21.59


636
ALA
CB
16.112
51.586
43.207
19.61


637
GLN
N
16.555
49.262
45.482
22.52


638
GLN
CA
15.859
48.190
46.212
23.75


639
GLN
C
14.447
47.831
45.617
21.92


640
GLN
O
13.548
47.415
46.324
23.13


641
GLN
CB
15.781
48.573
47.700
28.00


642
GLN
CG
17.090
48.375
48.482
37.73


643
GLN
CD
17.102
46.993
49.161
45.98


644
GLN
OE1
16.962
46.865
50.359
49.70


645
GLN
NE2
17.222
45.958
48.347
46.64


646
ARG
N
14.293
47.996
44.288
19.87


647
ARG
CA
13.167
47.433
43.520
15.56


648
ARG
C
13.671
46.530
42.369
15.93


649
ARG
O
14.589
46.892
41.649
19.66


650
ARG
CB
12.378
48.566
42.894
12.31


651
ARG
CG
11.026
48.114
42.359
8.59


652
ARG
CD
9.975
49.222
42.284
8.75


653
ARG
NE
9.454
49.581
43.583
9.44


654
ARG
CZ
8.781
50.712
43.804
13.29


655
ARG
NH1
8.507
51.573
42.868
14.59


656
ARG
NH2
8.376
50.970
44.997
14.52


657
SER
N
13.018
45.374
42.191
13.03


658
SER
CA
13.174
44.563
40.969
11.10


659
SER
C
11.905
44.484
40.133
9.85


660
SER
O
10.797
44.430
40.625
7.17


661
SER
CB
13.491
43.098
41.352
9.97


662
SER
OG
14.257
42.832
42.565
16.33


663
TYR
N
12.149
44.304
38.838
10.99


664
TYR
CA
11.059
43.986
37.924
11.25


665
TYR
C
11.428
42.738
37.134
11.69


666
TYR
O
12.600
42.426
36.947
12.93


667
TYR
CB
10.855
45.145
36.944
11.85


668
TYR
CG
11.048
46.504
37.543
11.61


669
TYR
CD1
12.330
46.990
37.697
13.15


670
TYR
CD2
9.974
47.284
37.928
10.09


671
TYR
CE1
12.574
48.223
38.239
12.30


672
TYR
CE2
10.189
48.561
38.453
11.52


673
TYR
CZ
11.477
49.041
38.615
11.57


674
TYR
OH
11.518
50.318
39.128
16.85


675
ILE
N
10.411
42.065
36.626
10.13


676
ILE
CA
10.683
41.103
35.561
10.15


677
ILE
C
10.210
41.646
34.208
11.23


678
ILE
O
9.017
41.882
34.001
14.10


679
ILE
CB
9.984
39.783
35.918
8.65


680
ILE
CG1
10.575
39.226
37.221
5.54


681
ILE
CG2
10.117
38.788
34.758
4.72


682
ILE
CD1
9.885
37.981
37.750
3.41


683
LEU
N
11.171
41.837
33.292
8.83


684
LEU
CA
10.757
42.279
31.952
8.27


685
LEU
C
10.642
41.089
31.042
9.63


686
LEU
O
11.563
40.274
30.925
10.20


687
LEU
CB
11.754
43.266
31.361
6.64


688
LEU
CG
11.554
44.667
31.933
5.33


689
LEU
CD1
12.441
45.790
31.363
7.20


690
LEU
CD2
11.164
44.814
33.411
7.37


691
THR
N
9.476
41.020
30.372
9.19


692
THR
CA
9.353
39.941
29.424
7.94


693
THR
C
8.748
40.395
28.068
7.09


694
THR
O
8.236
41.487
27.941
6.68


695
THR
CB
8.633
38.725
30.140
7.51


696
THR
OG1
8.460
37.446
29.475
10.84


697
THR
CG2
7.202
39.098
30.532
4.90


698
GLN
N
8.895
39.560
27.025
5.28


699
GLN
CA
8.176
39.853
25.785
4.05


700
GLN
C
6.657
39.538
25.856
8.34


701
GLN
O
6.182
38.810
26.707
9.07


702
GLN
CB
8.778
38.943
24.733
4.35


703
GLN
CG
8.435
37.461
24.941
3.62


704
GLN
CD
9.043
36.521
23.968
7.57


705
GLN
OE1
8.588
35.441
23.735
13.92


706
GLN
NE2
10.151
36.927
23.436
7.22


707
GLY
N
5.886
40.050
24.882
8.61


708
GLY
CA
4.495
39.635
24.802
6.03


709
GLY
C
4.380
38.143
24.529
6.11


710
GLY
O
4.839
37.652
23.504
6.83


711
PRO
N
3.737
37.417
25.464
7.87


712
PRO
CA
3.639
35.977
25.333
7.10


713
PRO
C
3.212
35.542
23.927
8.95


714
PRO
O
2.432
36.210
23.249
9.13


715
PRO
CB
2.617
35.533
26.387
7.90


716
PRO
CG
2.452
36.716
27.320
8.31


717
PRO
CD
3.076
37.939
26.655
8.22


718
LEU
N
3.826
34.451
23.462
11.50


719
LEU
CA
3.453
33.772
22.222
12.63


720
LEU
C
2.284
32.817
22.537
10.92


721
LEU
O
2.099
32.425
23.675
10.18


722
LEU
CB
4.653
32.966
21.630
12.16


723
LEU
CG
5.658
33.617
20.677
10.05


724
LEU
CD1
7.130
33.604
21.085
9.84


725
LEU
CD2
5.220
34.724
19.751
8.39


726
PRO
N
1.493
32.446
21.503
11.77


727
PRO
CA
0.410
31.494
21.723
12.03


728
PRO
C
0.830
30.158
22.433
13.54


729
PRO
O
0.089
29.551
23.183
15.14


730
PRO
CB
−0.132
31.242
20.320
9.15


731
PRO
CG
0.277
32.454
19.478
10.31


732
PRO
CD
1.572
32.919
20.123
10.84


733
ASN
N
2.100
29.779
22.259
13.43


734
ASN
CA
2.585
28.584
22.964
13.13


735
ASN
C
3.324
28.859
24.291
11.81


736
ASN
O
3.962
27.974
24.845
11.04


737
ASN
CB
3.496
27.799
22.046
13.99


738
ASN
CG
4.657
28.667
21.597
16.96


739
ASN
OD1
4.503
29.783
21.131
22.38


740
ASN
ND2
5.839
28.120
21.783
18.79


741
THR
N
3.286
30.095
24.782
9.69


742
THR
CA
4.037
30.277
26.042
9.51


743
THR
C
3.210
31.147
27.020
11.20


744
THR
O
3.752
31.735
27.945
11.31


745
THR
CB
5.272
31.194
25.696
8.41


746
THR
OG1
4.946
32.545
25.282
10.58


747
THR
CG2
6.132
30.535
24.591
5.31


748
CYS
N
1.877
31.177
26.815
12.27


749
CYS
CA
1.007
31.799
27.822
12.45


750
CYS
C
0.947
30.973
29.109
12.47


751
CYS
O
0.771
31.526
30.183
14.18


752
CYS
CB
−0.422
32.004
27.341
8.19


753
CYS
SG
−0.524
32.997
25.849
9.18


754
GLY
N
1.156
29.654
28.975
10.77


755
GLY
CA
1.293
28.814
30.180
10.51


756
GLY
C
2.589
29.054
30.979
13.69


757
GLY
O
2.584
29.199
32.182
14.84


758
HIS
N
3.719
29.198
30.259
14.08


759
HIS
CA
4.993
29.584
30.868
11.53


760
HIS
C
4.914
30.988
31.502
11.94


761
HIS
O
5.482
31.244
32.554
14.08


762
HIS
CB
6.065
29.732
29.789
10.46


763
HIS
CG
6.166
28.534
28.894
10.11


764
HIS
ND1
6.494
28.651
27.599
10.39


765
HIS
CD2
5.952
27.176
29.154
10.94


766
HIS
CE1
6.495
27.433
27.054
9.44


767
HIS
NE2
6.173
26.529
27.977
9.56


768
PHE
N
4.216
31.925
30.815
9.75


769
PHE
CA
4.084
33.301
31.370
8.97


770
PHE
C
3.385
33.272
32.732
9.22


771
PHE
O
3.896
33.785
33.709
10.50


772
PHE
CB
3.365
34.218
30.386
7.25


773
PHE
CG
3.083
35.612
30.896
7.78


774
PHE
CD1
1.951
35.897
31.664
11.43


775
PHE
CD2
3.909
36.683
30.568
9.65


776
PHE
CE1
1.682
37.195
32.100
9.78


777
PHE
CE2
3.605
37.988
30.955
8.16


778
PHE
CZ
2.499
38.243
31.737
5.91


779
TRP
N
2.224
32.595
32.770
9.57


780
TRP
CA
1.478
32.437
34.017
9.40


781
TRP
C
2.170
31.539
35.067
10.21


782
TRP
O
2.124
31.827
36.254
12.41


783
TRP
CB
0.044
32.007
33.682
8.88


784
TRP
CG
−0.686
33.205
33.102
10.66


785
TRP
CD1
−1.211
33.295
31.810
11.90


786
TRP
CD2
−0.933
34.478
33.751
10.70


787
TRP
NE1
−1.748
34.526
31.630
13.39


788
TRP
CE2
−1.595
35.307
32.790
11.80


789
TRP
CE3
−0.672
34.978
35.004
10.81


790
TRP
CZ2
−1.912
36.601
33.125
9.91


791
TRP
CZ3
−1.002
36.282
35.341
6.82


792
TRP
CH2
−1.615
37.109
34.389
9.18


793
GLU
N
2.885
30.502
34.607
11.17


794
GLU
CA
3.798
29.745
35.468
8.99


795
GLU
C
4.825
30.644
36.135
8.16


796
GLU
O
4.957
30.683
37.347
10.61


797
GLU
CB
4.501
28.631
34.698
9.22


798
GLU
CG
5.405
27.764
35.612
10.50


799
GLU
CD
6.236
26.726
34.837
11.31


800
GLU
OE1
6.063
26.619
33.627
15.64


801
GLU
OE2
7.056
26.019
35.406
11.72


802
MET
N
5.477
31.465
35.308
6.74


803
MET
CA
6.436
32.428
35.835
7.30


804
MET
C
5.812
33.362
36.919
9.58


805
MET
O
6.404
33.616
37.963
11.01


806
MET
CB
7.044
33.189
34.659
4.95


807
MET
CG
7.808
34.437
35.117
8.57


808
MET
SD
8.586
35.351
33.769
10.82


809
MET
CE
7.136
36.296
33.246
5.07


810
VAL
N
4.592
33.892
36.686
11.04


811
VAL
CA
4.040
34.817
37.683
10.24


812
VAL
C
3.700
34.069
38.978
12.49


813
VAL
O
3.978
34.571
40.066
12.79


814
VAL
CB
2.754
35.438
37.092
8.52


815
VAL
CG1
2.812
36.052
35.686
3.31


816
VAL
CG2
1.750
36.088
38.062
6.62


817
TRP
N
3.107
32.838
38.856
13.65


818
TRP
CA
2.909
31.996
40.053
12.02


819
TRP
C
4.227
31.749
40.844
11.70


820
TRP
O
4.326
32.034
42.034
12.54


821
TRP
CB
2.217
30.672
39.710
10.42


822
TRP
CG
1.863
29.951
41.001
12.86


823
TRP
CD1
2.696
29.101
41.739
14.68


824
TRP
CD2
0.644
30.071
41.772
14.87


825
TRP
NE1
2.072
28.715
42.886
15.11


826
TRP
CE2
0.810
29.275
42.935
15.72


827
TRP
CE3
−0.539
30.710
41.553
15.15


828
TRP
CZ2
−0.194
29.217
43.858
16.05


829
TRP
CZ3
−1.558
30.644
42.477
14.60


830
TRP
CH2
−1.389
29.889
43.623
17.06


831
GLU
N
5.226
31.223
40.140
12.34


832
GLU
CA
6.504
30.890
40.783
13.26


833
GLU
C
7.246
32.102
41.352
15.44


834
GLU
O
7.808
32.021
42.444
18.46


835
GLU
CB
7.401
30.155
39.785
11.02


836
GLU
CG
6.906
28.742
39.525
9.86


837
GLU
CD
7.513
28.097
38.292
10.94


838
GLU
OE1
8.355
28.663
37.634
13.74


839
GLU
OE2
7.119
26.985
38.017
12.82


840
GLN
N
7.186
33.233
40.614
15.26


841
GLN
CA
7.871
34.449
41.042
15.75


842
GLN
C
7.052
35.265
42.051
16.17


843
GLN
O
7.555
36.199
42.665
16.73


844
GLN
CB
8.228
35.289
39.806
16.31


845
GLN
CG
9.155
34.556
38.822
16.92


846
GLN
CD
10.425
34.083
39.552
19.20


847
GLN
OE1
11.001
34.783
40.362
19.09


848
GLN
NE2
10.810
32.870
39.299
15.74


849
LYS
N
5.771
34.861
42.227
15.25


850
LYS
CA
4.934
35.484
43.254
13.27


851
LYS
C
4.651
36.977
42.993
13.03


852
LYS
O
4.524
37.792
43.895
10.75


853
LYS
CB
5.567
35.249
44.622
16.84


854
LYS
CG
5.787
33.755
44.877
20.72


855
LYS
CD
6.097
33.446
46.349
23.31


856
LYS
CE
6.774
32.099
46.522
26.45


857
LYS
NZ
7.947
31.999
45.619
30.79


858
SER
N
4.552
37.327
41.701
14.11


859
SER
CA
4.152
38.693
41.351
13.84


860
SER
C
2.681
38.899
41.621
14.27


861
SER
O
1.854
38.015
41.464
13.39


862
SER
CB
4.462
38.899
39.829
13.28


863
SER
OG
5.745
38.417
39.369
13.97


864
ARG
N
2.389
40.117
42.068
15.30


865
ARG
CA
1.022
40.497
42.358
15.25


866
ARG
C
0.390
41.239
41.189
14.31


867
ARG
O
−0.817
41.375
41.116
11.90


868
ARG
CB
1.055
41.352
43.620
16.01


869
ARG
CG
−0.333
41.453
44.243
21.04


870
ARG
CD
−0.934
42.809
43.980
23.71


871
ARG
NE
−1.985
43.095
44.935
25.68


872
ARG
CZ
−3.145
42.448
44.880
25.46


873
ARG
NH1
−3.278
41.374
44.164
22.79


874
ARG
NH2
−4.168
42.930
45.529
27.74


875
GLY
N
1.276
41.733
40.301
12.62


876
GLY
CA
0.899
42.673
39.263
10.16


877
GLY
C
1.631
42.376
37.956
10.24


878
GLY
O
2.792
41.984
37.944
9.74


879
VAL
N
0.909
42.597
36.861
10.10


880
VAL
CA
1.554
42.588
35.545
9.04


881
VAL
C
1.189
43.904
34.860
7.92


882
VAL
O
0.021
44.276
34.795
8.52


883
VAL
CB
0.955
41.434
34.717
7.21


884
VAL
CG1
0.741
40.059
35.377
10.00


885
VAL
CG2
1.208
41.428
33.216
6.46


886
VAL
N
2.225
44.560
34.356
6.18


887
VAL
CA
2.002
45.766
33.558
5.67


888
VAL
C
2.204
45.440
32.090
5.05


889
VAL
O
3.294
45.104
31.685
8.26


890
VAL
CB
2.942
46.867
34.051
4.27


891
VAL
CG1
2.627
47.146
35.522
5.59


892
VAL
CG2
2.821
48.193
33.311
5.52


893
MET
N
1.129
45.564
31.315
6.05


894
MET
CA
1.132
45.435
29.850
6.12


895
MET
C
1.159
46.791
29.168
5.90


896
MET
O
0.263
47.591
29.379
6.94


897
MET
CB
−0.222
44.895
29.428
6.49


898
MET
CG
−0.347
44.620
27.938
5.59


899
MET
SD
−1.592
43.356
27.620
10.50


900
MET
CE
−1.470
43.249
25.807
2.00


901
LEU
N
2.146
47.028
28.319
5.40


902
LEU
CA
2.242
48.428
27.799
5.78


903
LEU
C
1.866
48.558
26.299
7.49


904
LEU
O
2.091
49.581
25.666
7.99


905
LEU
CB
3.632
48.997
28.075
6.33


906
LEU
CG
3.952
49.053
29.593
8.42


907
LEU
CD1
3.064
50.026
30.390
6.57


908
LEU
CD2
5.400
49.460
29.834
5.25


909
ASN
N
1.336
47.445
25.747
6.12


910
ASN
CA
1.077
47.367
24.327
8.78


911
ASN
C
−0.348
46.840
24.026
10.77


912
ASN
O
−0.979
46.296
24.907
11.62


913
ASN
CB
2.125
46.458
23.685
10.20


914
ASN
CG
1.956
45.019
24.175
10.50


915
ASN
OD1
1.469
44.137
23.509
13.52


916
ASN
ND2
2.370
44.830
25.401
11.44


917
ARG
N
−0.798
46.974
22.777
12.13


918
ARG
CA
−1.993
46.274
22.315
12.77


919
ARG
C
−1.619
44.915
21.703
11.64


920
ARG
O
−0.553
44.743
21.149
13.53


921
ARG
CB
−2.716
47.222
21.340
15.99


922
ARG
CG
−3.045
48.546
22.066
23.40


923
ARG
CD
−4.252
49.313
21.496
32.56


924
ARG
NE
−4.304
49.380
20.020
44.25


925
ARG
CZ
−3.229
49.594
19.246
50.26


926
ARG
NH1
−2.041
49.756
19.777
51.39


927
ARG
NH2
−3.324
49.640
17.948
53.49


928
VAL
N
−2.522
43.925
21.780
11.90


929
VAL
CA
−2.168
42.689
21.057
13.18


930
VAL
C
−2.076
42.945
19.536
12.04


931
VAL
O
−1.410
42.208
18.850
12.44


932
VAL
CB
−3.314
41.697
21.330
14.90


933
VAL
CG1
−3.544
41.230
22.786
14.45


934
VAL
CG2
−3.739
40.733
20.196
13.17


935
MET
N
−2.781
43.975
19.030
13.86


936
MET
CA
−2.503
44.415
17.669
16.37


937
MET
C
−1.936
45.845
17.600
15.93


938
MET
O
−2.532
46.816
18.063
15.73


939
MET
CB
−3.734
44.308
16.776
19.13


940
MET
CG
−3.319
44.384
15.289
25.05


941
MET
SD
−4.505
43.645
14.175
30.99


942
MET
CE
−4.816
45.133
13.287
28.20


943
GLU
N
−0.776
45.915
16.938
15.17


944
GLU
CA
−0.179
47.200
16.644
16.14


945
GLU
C
0.459
47.173
15.260
18.85


946
GLU
O
1.028
46.175
14.830
20.26


947
GLU
CB
0.888
47.527
17.679
15.90


948
GLU
CG
0.407
47.344
19.109
17.76


949
GLU
CD
1.416
47.771
20.137
18.82


950
GLU
OE1
2.568
47.438
19.990
16.03


951
GLU
OE2
1.021
48.466
21.072
15.57


952
LYS
N
0.322
48.325
14.571
22.41


953
LYS
CA
0.947
48.444
13.227
23.76


954
LYS
C
0.631
47.250
12.303
21.76


955
LYS
O
1.464
46.702
11.599
21.77


956
LYS
CB
2.450
48.721
13.386
24.05


957
LYS
CG
2.681
50.181
13.822
23.31


958
LYS
CD
3.794
50.330
14.847
25.30


959
LYS
CE
4.085
51.801
15.113
28.40


960
LYS
NZ
2.832
52.557
15.212
27.38


961
GLY
N
−0.656
46.844
12.413
20.87


962
GLY
CA
−1.177
45.815
11.522
19.66


963
GLY
C
−0.875
44.362
11.919
19.12


964
GLY
O
−1.358
43.436
11.269
19.90


965
SER
N
−0.076
44.207
12.978
17.43


966
SER
CA
0.409
42.896
13.385
16.48


967
SER
C
0.010
42.558
14.786
15.10


968
SER
O
−0.199
43.426
15.622
15.11


969
SER
CB
1.956
42.955
13.330
18.82


970
SER
OG
2.476
43.387
12.036
30.66


971
LEU
N
−0.028
41.228
14.996
14.24


972
LEU
CA
−0.222
40.624
16.300
13.02


973
LEU
C
1.075
40.659
17.114
12.02


974
LEU
O
2.026
39.930
16.888
12.03


975
LEU
CB
−0.717
39.195
16.092
13.63


976
LEU
CG
−2.160
39.215
15.545
10.24


977
LEU
CD1
−3.226
40.017
16.301
10.97


978
LEU
CD2
−2.646
37.927
14.916
9.61


979
LYS
N
1.105
41.571
18.084
11.18


980
LYS
CA
2.290
41.882
18.858
8.96


981
LYS
C
2.390
41.095
20.161
7.30


982
LYS
O
3.376
41.101
20.884
6.49


983
LYS
CB
2.258
43.376
19.126
12.36


984
LYS
CG
2.527
44.152
17.844
14.52


985
LYS
CD
3.978
44.105
17.484
16.12


986
LYS
CE
4.345
44.924
16.271
20.42


987
LYS
NZ
5.804
45.081
16.202
23.02


988
CYS
N
1.319
40.356
20.402
6.54


989
CYS
CA
1.256
39.673
21.686
10.66


990
CYS
C
0.100
38.668
21.635
14.07


991
CYS
O
−0.882
38.889
20.936
18.36


992
CYS
CB
1.133
40.710
22.839
9.20


993
CYS
SG
0.873
40.094
24.504
5.00


994
ALA
N
0.214
37.548
22.367
13.71


995
ALA
CA
−0.970
36.706
22.498
11.28


996
ALA
C
−2.054
37.332
23.451
13.57


997
ALA
O
−1.787
38.061
24.405
13.87


998
ALA
CB
−0.506
35.347
22.988
5.96


999
GLN
N
−3.315
36.986
23.148
13.22


1000
GLN
CA
−4.355
37.267
24.134
11.86


1001
GLN
C
−4.194
36.315
25.338
9.90


1002
GLN
O
−4.748
35.227
25.329
8.51


1003
GLN
CB
−5.696
36.958
23.442
11.64


1004
GLN
CG
−6.901
37.307
24.331
12.96


1005
GLN
CD
−6.930
38.782
24.786
15.38


1006
GLN
OE1
−7.275
39.155
25.885
18.48


1007
GLN
NE2
−6.501
39.645
23.923
10.76


1008
TYR
N
−3.353
36.690
26.311
10.20


1009
TYR
CA
−2.959
35.652
27.305
11.34


1010
TYR
C
−3.874
35.622
28.587
10.00


1011
TYR
O
−3.692
34.809
29.480
12.22


1012
TYR
CB
−1.451
35.764
27.671
9.57


1013
TYR
CG
−1.092
37.093
28.295
10.61


1014
TYR
CD1
−1.112
37.261
29.674
11.35


1015
TYR
CD2
−0.748
38.189
27.492
10.24


1016
TYR
CE1
−0.865
38.489
30.277
10.01


1017
TYR
CE2
−0.500
39.429
28.066
8.22


1018
TYR
CZ
−0.564
39.588
29.448
8.65


1019
TYR
OH
−0.317
40.841
29.935
7.28


1020
TRP
N
−4.815
36.557
28.642
9.43


1021
TRP
CA
−5.714
36.690
29.792
10.16


1022
TRP
C
−7.175
36.690
29.287
10.75


1023
TRP
O
−7.442
37.154
28.187
8.67


1024
TRP
CB
−5.341
37.945
30.612
8.10


1025
TRP
CG
−5.788
39.222
29.929
8.50


1026
TRP
CD1
−6.970
39.931
30.199
9.41


1027
TRP
CD2
−5.138
39.917
28.835
8.04


1028
TRP
NE1
−7.089
40.994
29.356
8.02


1029
TRP
CE2
−5.979
41.032
28.508
8.86


1030
TRP
CE3
−3.990
39.680
28.138
6.23


1031
TRP
CZ2
−5.626
41.863
27.469
7.39


1032
TRP
CZ3
−3.641
40.518
27.068
8.40


1033
TRP
CH2
−4.457
41.614
26.747
8.65


1034
PRO
N
−8.137
36.145
30.127
11.94


1035
PRO
CA
−9.538
36.107
29.746
11.58


1036
PRO
C
10.158
37.512
29.637
14.25


1037
PRO
O
10.022
38.396
30.486
14.80


1038
PRO
CB
10.225
35.238
30.819
8.41


1039
PRO
CG
−9.311
35.278
32.027
5.08


1040
PRO
CD
−7.939
35.615
31.474
10.33


1041
GLN
N
10.892
37.626
28.524
15.45


1042
GLN
CA
11.657
38.851
28.328
18.38


1043
GLN
C
13.068
38.858
28.949
19.02


1044
GLN
O
13.747
39.861
28.892
20.54


1045
GLN
CB
11.682
39.166
26.841
20.69


1046
GLN
CG
10.255
39.453
26.327
27.58


1047
GLN
CD
10.336
39.675
24.835
28.97


1048
GLN
OE1
10.447
38.767
24.036
27.29


1049
GLN
NE2
10.375
40.949
24.506
28.60


1050
LYS
N
13.516
37.738
29.523
19.10


1051
LYS
CA
14.764
37.856
30.269
18.50


1052
LYS
C
14.946
36.717
31.217
15.91


1053
LYS
O
14.342
35.680
31.035
16.84


1054
LYS
CB
15.921
37.842
29.309
24.10


1055
LYS
CG
15.932
36.706
28.297
25.36


1056
LYS
CD
16.993
36.968
27.238
29.33


1057
LYS
CE
17.243
38.464
27.014
37.08


1058
LYS
NZ
18.344
38.699
26.095
42.94


1059
GLU
N
15.801
36.951
32.206
14.50


1060
GLU
CA
15.976
36.171
33.393
14.90


1061
GLU
C
16.338
34.709
33.088
18.20


1062
GLU
O
15.719
33.790
33.632
21.55


1063
GLU
CB
17.056
36.856
34.217
15.32


1064
GLU
CG
16.575
38.151
34.874
13.30


1065
GLU
CD
16.724
39.424
34.004
16.29


1066
GLU
OE1
16.616
39.376
32.782
16.80


1067
GLU
OE2
16.964
40.491
34.568
16.60


1068
GLU
N
17.317
34.475
32.183
19.29


1069
GLU
CA
17.820
33.133
31.855
19.57


1070
GLU
C
16.760
32.233
31.213
21.30


1071
GLU
O
16.888
31.007
31.232
20.15


1072
GLU
CB
18.964
33.205
30.827
18.63


1073
GLU
CG
19.852
34.414
31.027
16.44


1074
GLU
CD
19.393
35.654
30.276
16.06


1075
GLU
OE1
19.651
35.750
29.079
17.52


1076
GLU
OE2
18.763
36.522
30.864
15.56


1077
LYS
N
15.763
32.878
30.564
21.95


1078
LYS
CA
14.806
32.104
29.783
24.05


1079
LYS
C
13.376
32.240
30.376
24.41


1080
LYS
O
12.539
32.989
29.869
24.56


1081
LYS
CB
14.884
32.562
28.310
26.00


1082
LYS
CG
16.297
32.545
27.708
32.43


1083
LYS
CD
16.445
31.919
26.320
39.12


1084
LYS
CE
15.519
30.736
26.063
47.59


1085
LYS
NZ
16.271
29.672
25.392
51.15


1086
GLU
N
13.140
31.494
31.483
24.94


1087
GLU
CA
11.782
31.372
32.025
23.85


1088
GLU
C
10.831
30.682
31.032
20.25


1089
GLU
O
11.227
29.985
30.119
19.30


1090
GLU
CB
11.754
30.531
33.308
26.32


1091
GLU
CG
13.084
30.345
34.016
32.27


1092
GLU
CD
13.812
29.168
33.377
33.00


1093
GLU
OE1
13.258
28.077
33.359
32.06


1094
GLU
OE2
14.929
29.369
32.909
35.48


1095
MET
N
−9.550
30.894
31.280
17.49


1096
MET
CA
−8.526
30.188
30.550
15.38


1097
MET
C
−7.902
29.097
31.442
16.86


1098
MET
O
−7.471
29.361
32.554
18.95


1099
MET
CB
−7.489
31.239
30.146
12.45


1100
MET
CG
−8.055
32.218
29.122
11.06


1101
MET
SD
−6.888
33.465
28.615
15.30


1102
MET
CE
−5.835
32.442
27.602
13.48


1103
ILE
N
−7.819
27.879
30.942
15.12


1104
ILE
CA
−6.944
26.908
31.605
16.59


1105
ILE
C
−5.708
26.614
30.770
17.15


1106
ILE
O
−5.788
26.242
29.614
19.86


1107
ILE
CB
−7.708
25.631
31.971
18.08


1108
ILE
CG1
−8.632
25.919
33.163
23.46


1109
ILE
CG2
−6.764
24.493
32.352
17.34


1110
ILE
CD1
10.089
25.551
32.914
24.91


1111
PHE
N
−4.558
26.751
31.426
16.66


1112
PHE
CA
−3.307
26.461
30.755
16.55


1113
PHE
C
−2.838
25.024
31.123
19.38


1114
PHE
O
−2.330
24.746
32.201
19.28


1115
PHE
CB
−2.336
27.588
31.105
12.36


1116
PHE
CG
−2.824
28.944
30.818
10.57


1117
PHE
CD1
−2.749
29.439
29.534
8.04


1118
PHE
CD2
−3.334
29.723
31.855
11.55


1119
PHE
CE1
−3.201
30.723
29.284
10.42


1120
PHE
CE2
−3.787
31.007
31.608
11.87


1121
PHE
CZ
−3.719
31.506
30.311
12.28


1122
GLU
N
−3.116
24.104
30.205
21.82


1123
GLU
CA
−3.039
22.720
30.661
25.19


1124
GLU
C
−1.584
22.256
30.878
24.14


1125
GLU
O
−1.290
21.361
31.659
25.33


1126
GLU
CB
−3.639
21.787
29.605
31.07


1127
GLU
CG
−5.166
21.765
29.396
39.94


1128
GLU
CD
−5.454
20.639
28.364
48.24


1129
GLU
OE1
−5.364
20.905
27.164
52.05


1130
GLU
OE2
−5.724
19.507
28.772
51.99


1131
ASP
N
−0.697
22.914
30.136
23.00


1132
ASP
CA
0.712
22.482
30.155
22.21


1133
ASP
C
1.446
22.782
31.508
20.47


1134
ASP
O
2.261
22.031
32.033
19.77


1135
ASP
CB
1.332
23.130
28.915
21.00


1136
ASP
CG
1.430
24.643
29.079
22.61


1137
ASP
OD1
0.486
25.282
29.556
26.49


1138
ASP
OD2
2.454
25.190
28.734
21.60


1139
THR
N
1.068
23.914
32.079
19.14


1140
THR
CA
1.645
24.175
33.404
16.22


1141
THR
C
0.561
24.054
34.479
18.50


1142
THR
O
0.848
24.327
35.628
20.38


1143
THR
CB
2.051
25.710
33.412
14.66


1144
THR
OG1
0.989
26.641
33.065
13.92


1145
THR
CG2
3.261
25.983
32.480
11.30


1146
ASN
N
−0.686
23.637
34.105
19.33


1147
ASN
CA
−1.730
23.331
35.094
19.95


1148
ASN
C
−2.154
24.539
35.987
21.85


1149
ASN
O
−2.161
24.482
37.214
22.33


1150
ASN
CB
−1.180
22.269
36.021
24.72


1151
ASN
CG
−2.334
21.494
36.646
27.53


1152
ASN
OD1
−3.342
21.190
36.060
30.68


1153
ASN
ND2
−2.193
21.200
37.881
26.04


1154
LEU
N
−2.484
25.635
35.297
22.78


1155
LEU
CA
−2.886
26.899
35.936
22.24


1156
LEU
C
−4.265
27.315
35.376
22.59


1157
LEU
O
−4.561
27.167
34.194
23.95


1158
LEU
CB
−1.875
28.025
35.599
21.01


1159
LEU
CG
−0.701
28.404
36.548
17.04


1160
LEU
CD1
0.610
28.303
35.804
13.07


1161
LEU
CD2
−0.612
27.764
37.930
14.04


1162
LYS
N
−5.087
27.901
36.222
20.53


1163
LYS
CA
−6.322
28.485
35.725
17.91


1164
LYS
C
−6.339
30.003
35.942
17.68


1165
LYS
O
−5.903
30.515
36.958
16.29


1166
LYS
CB
−7.441
27.691
36.368
17.25


1167
LYS
CG
−8.807
28.050
35.869
18.58


1168
LYS
CD
−9.895
27.178
36.443
22.19


1169
LYS
CE
11.140
27.885
36.932
22.34


1170
LYS
NZ
11.879
26.984
37.836
24.46


1171
LEU
N
−6.846
30.705
34.934
17.39


1172
LEU
CA
−7.006
32.157
34.943
15.35


1173
LEU
C
−8.477
32.621
34.637
16.31


1174
LEU
O
−9.075
32.259
33.636
16.43


1175
LEU
CB
−5.961
32.752
34.009
12.86


1176
LEU
CG
−5.853
34.284
34.126
9.27


1177
LEU
CD1
−5.021
34.787
32.956
8.45


1178
LEU
CD2
−5.200
34.687
35.454
9.53


1179
THR
N
−9.012
33.479
35.526
13.25


1180
THR
CA
10.363
34.063
35.463
12.10


1181
THR
C
10.355
35.563
35.597
13.46


1182
THR
O
−9.718
36.088
36.499
15.11


1183
THR
CB
11.097
33.461
36.694
12.89


1184
THR
OG1
10.946
32.013
36.745
11.16


1185
THR
CG2
12.589
33.673
36.530
13.73


1186
LEU
N
11.097
36.253
34.707
12.69


1187
LEU
CA
11.361
37.680
34.900
13.21


1188
LEU
C
12.268
37.840
36.109
16.36


1189
LEU
O
13.383
37.337
36.138
17.33


1190
LEU
CB
12.105
38.280
33.697
9.27


1191
LEU
CG
12.355
39.790
33.774
5.96


1192
LEU
CD1
13.113
40.189
32.520
3.05


1193
LEU
CD2
11.034
40.574
33.866
2.04


1194
ILE
N
11.767
38.531
37.113
16.98


1195
ILE
CA
12.711
38.814
38.209
16.56


1196
ILE
C
13.488
40.095
37.970
15.67


1197
ILE
O
14.677
40.183
38.224
16.31


1198
ILE
CB
12.058
38.673
39.567
14.46


1199
ILE
CG1
11.521
37.227
39.718
13.21


1200
ILE
CG2
13.057
39.124
40.658
11.57


1201
ILE
CD1
12.570
36.104
39.539
7.88


1202
SER
N
12.769
41.053
37.410
16.03


1203
SER
CA
13.492
42.181
36.859
17.37


1204
SER
C
12.449
43.133
36.298
19.23


1205
SER
O
11.276
42.946
36.557
19.21


1206
SER
CB
14.107
42.990
38.027
20.04


1207
SER
OG
13.123
43.511
39.003
20.18


1208
GLU
N
12.886
44.193
35.634
22.29


1209
GLU
CA
11.982
45.230
35.140
23.93


1210
GLU
C
12.557
46.663
35.235
23.31


1211
GLU
O
13.754
46.861
35.283
27.00


1212
GLU
CB
11.701
44.924
33.697
24.38


1213
GLU
CG
12.961
44.717
32.896
25.56


1214
GLU
CD
12.581
44.588
31.426
31.45


1215
GLU
OE1
11.402
44.721
31.054
32.20


1216
GLU
OE2
13.483
44.345
30.651
36.07


1217
ASP
N
11.671
47.634
35.279
21.18


1218
ASP
CA
11.995
49.030
35.441
17.82


1219
ASP
C
11.395
49.764
34.225
18.72


1220
ASP
O
10.200
50.051
34.108
20.93


1221
ASP
CB
11.443
49.430
36.814
22.34


1222
ASP
CG
11.406
50.932
37.034
28.58


1223
ASP
OD1
12.354
51.602
36.636
27.70


1224
ASP
OD2
10.412
51.436
37.597
33.90


1225
ILE
N
12.306
49.980
33.282
18.31


1226
ILE
CA
11.933
50.554
32.008
19.98


1227
ILE
C
11.874
52.099
32.025
20.84


1228
ILE
O
12.850
52.781
32.267
20.15


1229
ILE
CB
12.946
50.053
30.978
20.01


1230
ILE
CG1
12.853
48.540
30.856
20.02


1231
ILE
CG2
12.762
50.696
29.607
19.35


1232
ILE
CD1
13.722
47.987
29.733
21.08


1233
LYS
N
10.700
52.617
31.682
22.09


1234
LYS
CA
10.548
54.069
31.550
21.26


1235
LYS
C
10.289
54.430
30.108
20.78


1236
LYS
O
10.038
53.563
29.266
22.79


1237
LYS
CB
−9.402
54.433
32.459
22.27


1238
LYS
CG
−9.721
54.009
33.868
22.36


1239
LYS
CD
10.326
55.177
34.630
25.91


1240
LYS
CE
10.825
54.813
36.002
28.42


1241
LYS
NZ
11.309
56.052
36.589
30.51


1242
THR
N
10.327
55.686
29.733
19.62


1243
THR
CA
10.249
56.059
28.237
20.98


1244
THR
C
−8.822
55.510
27.732
20.84


1245
THR
O
−8.780
55.122
26.657
22.93


1246
THR
CB
−9.822
57.568
28.309
19.41


1247
THR
OG1
−8.833
57.806
29.314
22.97


1248
THR
CG2
11.069
58.348
28.636
24.19


1249
TYR
N
−7.719
55.518
28.646
20.25


1250
TYR
CA
−6.458
55.219
28.007
18.72


1251
TYR
C
−5.770
53.922
28.602
18.44


1252
TYR
O
−4.685
53.476
28.203
20.29


1253
TYR
CB
−5.607
56.494
28.042
16.14


1254
TYR
CG
−4.897
56.888
29.314
13.33


1255
TYR
CD1
−5.465
57.864
30.081
14.09


1256
TYR
CD2
−3.682
56.427
29.721
13.30


1257
TYR
CE1
−5.016
58.191
31.311
17.45


1258
TYR
CE2
−3.090
56.866
30.874
19.22


1259
TYR
CZ
−3.767
57.715
31.696
19.65


1260
TYR
OH
−3.079
58.078
32.801
20.24


1261
TYR
N
−6.461
53.351
29.591
15.06


1262
TYR
CA
−5.915
52.151
30.228
14.61


1263
TYR
C
−7.010
51.388
30.962
15.66


1264
TYR
O
−8.023
51.956
31.320
17.43


1265
TYR
CB
−4.719
52.522
31.134
15.82


1266
TYR
CG
−5.118
53.115
32.443
19.10


1267
TYR
CD1
−5.449
52.289
33.528
21.07


1268
TYR
CD2
−5.158
54.491
32.606
21.69


1269
TYR
CE1
−5.830
52.813
34.755
19.08


1270
TYR
CE2
−5.580
55.003
33.823
22.03


1271
TYR
CZ
−5.883
54.185
34.902
20.70


1272
TYR
OH
−6.221
54.746
36.125
20.35


1273
THR
N
−6.777
50.103
31.213
13.79


1274
THR
CA
−7.774
49.326
31.968
14.01


1275
THR
C
−7.068
48.551
33.024
13.51


1276
THR
O
−6.050
47.935
32.736
12.55


1277
THR
CB
−8.369
48.336
30.922
15.24


1278
THR
OG1
−9.115
48.941
29.853
15.88


1279
THR
CG2
−9.278
47.291
31.615
12.04


1280
VAL
N
−7.636
48.525
34.247
13.29


1281
VAL
CA
−7.079
47.585
35.204
14.30


1282
VAL
C
−8.024
46.398
35.369
14.29


1283
VAL
O
−9.217
46.546
35.469
15.36


1284
VAL
CB
−6.887
48.311
36.548
13.88


1285
VAL
CG1
−6.372
49.756
36.536
8.84


1286
VAL
CG2
−6.537
47.465
37.788
13.68


1287
ARG
N
−7.465
45.214
35.420
12.81


1288
ARG
CA
−8.229
44.025
35.644
11.72


1289
ARG
C
−7.772
43.342
36.930
12.76


1290
ARG
O
−6.620
43.342
37.320
12.68


1291
ARG
CB
−8.045
43.128
34.450
11.12


1292
ARG
CG
−8.286
43.859
33.139
15.30


1293
ARG
CD
−8.261
42.904
31.963
20.03


1294
ARG
NE
−8.786
43.590
30.765
23.64


1295
ARG
CZ
−7.985
44.278
29.965
22.07


1296
ARG
NH1
−6.692
44.288
30.189
21.13


1297
ARG
NH2
−8.468
44.954
28.976
24.55


1298
GLN
N
−8.730
42.732
37.569
15.02


1299
GLN
CA
−8.427
41.791
38.595
17.49


1300
GLN
C
−8.600
40.390
38.060
15.96


1301
GLN
O
−9.647
40.036
37.541
14.32


1302
GLN
CB
−9.382
42.030
39.713
22.81


1303
GLN
CG
−9.262
41.053
40.854
32.87


1304
GLN
CD
10.405
41.347
41.813
39.46


1305
GLN
OE1
11.408
41.967
41.482
41.19


1306
GLN
NE2
10.187
40.875
43.013
42.57


1307
LEU
N
−7.538
39.630
38.194
15.65


1308
LEU
CA
−7.498
38.264
37.718
15.53


1309
LEU
C
−7.483
37.312
38.917
15.62


1310
LEU
O
−7.009
37.654
39.984
17.25


1311
LEU
CB
−6.202
38.112
36.903
16.62


1312
LEU
CG
−6.242
38.575
35.434
14.27


1313
LEU
CD1
−4.942
38.991
34.790
16.50


1314
LEU
CD2
−7.496
39.201
34.857
12.30


1315
GLU
N
−7.982
36.101
38.711
15.87


1316
GLU
CA
−7.649
35.059
39.670
14.28


1317
GLU
C
−6.819
34.006
38.952
12.82


1318
GLU
O
−7.183
33.521
37.900
11.62


1319
GLU
CB
−8.912
34.480
40.323
15.74


1320
GLU
CG
−8.504
33.348
41.273
20.52


1321
GLU
CD
−9.616
32.843
42.174
22.26


1322
GLU
OE1
10.040
33.589
43.047
26.87


1323
GLU
OE2
10.020
31.708
42.012
16.51


1324
LEU
N
−5.679
33.708
39.578
13.74


1325
LEU
CA
−4.780
32.673
39.137
14.23


1326
LEU
C
−4.851
31.471
40.119
16.97


1327
LEU
O
−4.491
31.577
41.289
13.98


1328
LEU
CB
−3.391
33.307
39.131
13.18


1329
LEU
CG
−2.359
32.718
38.152
14.58


1330
LEU
CD1
−2.685
31.494
37.300
13.64


1331
LEU
CD2
−0.889
32.995
38.428
15.94


1332
GLU
N
−5.312
30.327
39.601
18.45


1333
GLU
CA
−5.299
29.116
40.366
18.22


1334
GLU
C
−4.243
28.118
39.888
19.24


1335
GLU
O
−4.250
27.596
38.789
17.31


1336
GLU
CB
−6.667
28.458
40.354
18.17


1337
GLU
CG
−6.781
27.377
41.470
20.37


1338
GLU
CD
−8.058
26.570
41.332
22.37


1339
GLU
OE1
−8.995
26.977
40.666
21.04


1340
GLU
OE2
−8.108
25.474
41.879
25.85


1341
ASN
N
−3.345
27.828
40.804
22.37


1342
ASN
CA
−2.546
26.649
40.584
25.92


1343
ASN
C
−3.387
25.377
40.755
25.53


1344
ASN
O
−3.572
24.897
41.861
25.67


1345
ASN
CB
−1.325
26.765
41.500
27.66


1346
ASN
CG
−0.601
25.427
41.717
27.77


1347
ASN
OD1
−1.077
24.341
41.436
27.56


1348
ASN
ND2
0.571
25.533
42.244
29.56


1349
LEU
N
−3.807
24.821
39.627
23.83


1350
LEU
CA
−4.652
23.629
39.641
22.45


1351
LEU
C
−4.106
22.430
40.435
24.96


1352
LEU
O
−4.848
21.603
40.937
26.15


1353
LEU
CB
−4.919
23.245
38.197
16.54


1354
LEU
CG
−6.200
23.824
37.584
15.77


1355
LEU
CD1
−6.355
23.781
36.061
13.72


1356
LEU
CD2
−6.966
24.930
38.291
12.99


1357
THR
N
−2.783
22.364
40.547
26.74


1358
THR
CA
−2.184
21.257
41.276
27.87


1359
THR
C
−2.387
21.269
42.779
29.27


1360
THR
O
−2.324
20.235
43.438
30.62


1361
THR
CB
−0.656
21.271
40.960
28.76


1362
THR
OG1
−0.222
21.276
39.580
28.70


1363
THR
CG2
0.076
20.197
41.798
28.43


1364
THR
N
−2.626
22.437
43.328
28.69


1365
THR
CA
−2.904
22.402
44.775
28.99


1366
THR
C
−4.201
23.179
45.033
32.17


1367
THR
O
−4.673
23.210
46.146
34.29


1368
THR
CB
−1.808
23.352
45.374
25.58


1369
THR
OG1
−1.906
24.712
44.893
24.80


1370
THR
CG2
−0.413
22.844
44.960
21.97


1371
GLN
N
−4.726
23.838
43.975
34.19


1372
GLN
CA
−5.903
24.683
44.149
36.02


1373
GLN
C
−5.651
25.904
45.068
34.54


1374
GLN
O
−6.560
26.502
45.630
34.82


1375
GLN
CB
−7.056
23.797
44.633
40.16


1376
GLN
CG
−7.447
22.737
43.605
46.76


1377
GLN
CD
−8.777
22.111
44.000
50.73


1378
GLN
OE1
−9.050
21.806
45.145
50.25


1379
GLN
NE2
−9.586
21.893
42.985
53.71


1380
GLU
N
−4.364
26.264
45.184
33.22


1381
GLU
CA
−4.084
27.590
45.723
33.18


1382
GLU
C
−4.526
28.672
44.740
30.34


1383
GLU
O
−4.574
28.507
43.524
28.93


1384
GLU
CB
−2.597
27.807
45.960
37.35


1385
GLU
CG
−2.029
27.073
47.151
45.79


1386
GLU
CD
−0.503
27.118
47.092
53.23


1387
GLU
OE1
0.090
28.186
47.253
54.41


1388
GLU
OE2
0.110
26.083
46.854
58.44


1389
THR
N
−4.771
29.824
45.341
27.29


1390
THR
CA
−5.321
30.882
44.519
21.75


1391
THR
C
−4.702
32.231
44.866
20.39


1392
THR
O
−4.480
32.572
46.024
21.88


1393
THR
CB
−6.901
30.855
44.831
20.91


1394
THR
OG1
−7.887
30.317
43.926
18.30


1395
THR
CG2
−7.402
32.239
45.242
22.13


1396
ARG
N
−4.478
33.010
43.805
17.74


1397
ARG
CA
−3.917
34.344
44.023
15.94


1398
ARG
C
−4.593
35.365
43.131
15.58


1399
ARG
O
−4.922
35.078
41.994
14.33


1400
ARG
CB
−2.434
34.314
43.653
16.13


1401
ARG
CG
−1.673
33.304
44.487
18.13


1402
ARG
CD
−0.197
33.503
44.382
18.87


1403
ARG
NE
0.471
32.485
45.132
20.71


1404
ARG
CZ
1.666
32.149
44.780
21.27


1405
ARG
NH1
2.351
32.800
43.866
19.60


1406
ARG
NH2
2.163
31.120
45.349
22.46


1407
GLU
N
−4.737
36.564
43.664
16.20


1408
GLU
CA
−5.232
37.648
42.820
17.96


1409
GLU
C
−4.066
38.466
42.226
18.25


1410
GLU
O
−3.223
39.023
42.925
19.75


1411
GLU
CB
−6.054
38.623
43.649
20.78


1412
GLU
CG
−6.513
39.851
42.845
23.52


1413
GLU
CD
−6.777
40.984
43.840
31.18


1414
GLU
OE1
−5.867
41.331
44.491
35.95


1415
GLU
OE2
−7.849
41.495
43.990
33.07


1416
ILE
N
−4.131
38.557
40.902
16.64


1417
ILE
CA
−3.169
39.310
40.109
12.04


1418
ILE
C
−3.880
40.515
39.527
11.07


1419
ILE
O
−4.862
40.403
38.819
11.62


1420
ILE
CB
−2.704
38.444
38.926
9.49


1421
ILE
CG1
−2.292
37.027
39.359
8.19


1422
ILE
CG2
−1.679
39.155
38.027
6.71


1423
ILE
CD1
−1.062
36.953
40.271
8.86


1424
LEU
N
−3.314
41.663
39.796
12.20


1425
LEU
CA
−3.765
42.894
39.153
11.34


1426
LEU
C
−3.068
43.084
37.797
10.98


1427
LEU
O
−1.855
43.017
37.679
11.20


1428
LEU
CB
−3.376
43.996
40.135
11.87


1429
LEU
CG
−4.459
44.428
41.136
14.45


1430
LEU
CD1
−3.851
45.049
42.374
13.48


1431
LEU
CD2
−5.510
43.382
41.494
14.58


1432
HIS
N
−3.887
43.335
36.774
11.21


1433
HIS
CA
−3.409
43.599
35.405
10.35


1434
HIS
C
−3.599
45.056
35.037
11.82


1435
HIS
O
−4.720
45.529
34.960
13.04


1436
HIS
CB
−4.223
42.719
34.475
10.25


1437
HIS
CG
−3.735
42.604
33.061
5.26


1438
HIS
ND1
−4.371
43.183
32.017
4.31


1439
HIS
CD2
−2.622
41.907
32.605
3.49


1440
HIS
CE1
−3.660
42.851
30.935
4.28


1441
HIS
NE2
−2.608
42.086
31.264
4.14


1442
PHE
N
−2.489
45.762
34.785
10.90


1443
PHE
CA
−2.577
47.192
34.424
10.08


1444
PHE
C
−2.213
47.405
32.956
10.93


1445
PHE
O
−1.070
47.258
32.553
12.60


1446
PHE
CB
−1.586
48.018
35.254
8.89


1447
PHE
CG
−1.856
47.856
36.714
10.34


1448
PHE
CD1
−1.223
46.858
37.441
9.37


1449
PHE
CD2
−2.739
48.705
37.357
12.07


1450
PHE
CE1
−1.474
46.722
38.787
8.64


1451
PHE
CE2
−2.995
48.564
38.714
7.54


1452
PHE
CZ
−2.359
47.577
39.417
6.90


1453
HIS
N
−3.227
47.745
32.158
10.22


1454
HIS
CA
−3.060
47.678
30.720
10.82


1455
HIS
C
−3.094
49.072
30.056
11.67


1456
HIS
O
−4.145
49.698
29.957
13.22


1457
HIS
CB
−4.194
46.789
30.220
11.88


1458
HIS
CG
−4.060
46.522
28.750
9.09


1459
HIS
ND1
−3.037
46.925
27.987
14.21


1460
HIS
CD2
−4.958
45.845
27.938
9.60


1461
HIS
CE1
−3.331
46.498
26.751
10.85


1462
HIS
NE2
−4.488
45.829
26.687
11.12


1463
TYR
N
−1.914
49.518
29.591
11.21


1464
TYR
CA
−1.813
50.801
28.897
12.13


1465
TYR
C
−2.155
50.619
27.389
13.01


1466
TYR
O
−1.497
49.865
26.675
12.08


1467
TYR
CB
−0.388
51.305
29.131
11.51


1468
TYR
CG
−0.235
52.799
29.078
14.44


1469
TYR
CD1
−0.475
53.489
27.919
15.45


1470
TYR
CD2
0.267
53.497
30.164
13.74


1471
TYR
CE1
−0.140
54.860
27.837
15.14


1472
TYR
CE2
0.460
54.871
30.142
13.53


1473
TYR
CZ
0.229
55.578
28.981
12.44


1474
TYR
OH
0.435
56.939
28.993
13.99


1475
THR
N
−3.213
51.285
26.911
13.59


1476
THR
CA
−3.606
50.873
25.519
15.13


1477
THR
C
−3.481
52.067
24.538
16.95


1478
THR
O
−3.906
51.956
23.403
20.50


1479
THR
CB
−5.144
50.574
25.606
13.16


1480
THR
OG1
−5.954
51.612
26.206
15.62


1481
THR
CG2
−5.433
49.321
26.462
10.17


1482
THR
N
−2.858
53.182
24.942
15.57


1483
THR
CA
−2.577
54.214
23.880
14.73


1484
THR
C
−1.085
54.620
23.940
15.24


1485
THR
O
−0.720
55.737
23.634
16.37


1486
THR
CB
−3.210
55.519
24.477
15.29


1487
THR
OG1
−2.750
55.685
25.838
16.09


1488
THR
CG2
−4.765
55.520
24.411
14.63


1489
TRP
N
−0.197
53.698
24.382
13.79


1490
TRP
CA
1.223
53.979
24.245
12.12


1491
TRP
C
1.772
53.276
22.951
11.93


1492
TRP
O
1.876
52.056
22.904
14.64


1493
TRP
CB
1.906
53.454
25.513
13.19


1494
TRP
CG
3.394
53.773
25.583
10.47


1495
TRP
CD1
4.221
54.197
24.541
8.59


1496
TRP
CD2
4.228
53.714
26.768
11.45


1497
TRP
NE1
5.472
54.391
24.988
9.33


1498
TRP
CE2
5.529
54.103
26.358
11.57


1499
TRP
CE3
3.999
53.379
28.077
8.59


1500
TRP
CZ2
6.546
54.155
27.292
8.09


1501
TRP
CZ3
5.036
53.437
29.007
7.89


1502
TRP
CH2
6.317
53.825
28.620
3.96


1503
PRO
N
2.127
54.031
21.860
11.54


1504
PRO
CA
2.430
53.374
20.577
9.51


1505
PRO
C
3.765
52.621
20.539
9.46


1506
PRO
O
4.738
53.105
21.091
9.47


1507
PRO
CB
2.388
54.494
19.532
5.29


1508
PRO
CG
1.818
55.684
20.278
4.86


1509
PRO
CD
2.158
55.495
21.745
8.47


1510
ASP
N
3.775
51.454
19.864
8.54


1511
ASP
CA
5.035
50.736
19.645
10.50


1512
ASP
C
6.154
51.662
19.076
12.96


1513
ASP
O
5.907
52.405
18.129
15.10


1514
ASP
CB
4.794
49.507
18.750
10.62


1515
ASP
CG
5.909
48.497
18.955
11.09


1516
ASP
OD1
6.834
48.771
19.704
16.40


1517
ASP
OD2
5.840
47.423
18.386
12.44


1518
PHE
N
7.320
51.664
19.747
12.20


1519
PHE
CA
8.430
52.587
19.427
11.72


1520
PHE
C
8.102
54.085
19.493
12.78


1521
PHE
O
8.865
54.904
18.986
12.60


1522
PHE
CB
9.015
52.330
18.045
9.10


1523
PHE
CG
9.636
50.969
17.921
9.42


1524
PHE
CD1
10.917
50.751
18.407
7.65


1525
PHE
CD2
8.923
49.930
17.329
7.68


1526
PHE
CE1
11.479
49.496
18.292
7.82


1527
PHE
CE2
9.488
48.677
17.203
7.43


1528
PHE
CZ
10.762
48.468
17.686
6.08


1529
GLY
N
6.979
54.401
20.157
11.81


1530
GLY
CA
6.677
55.764
20.535
10.61


1531
GLY
C
6.660
55.972
22.034
13.38


1532
GLY
O
7.313
55.303
22.839
14.97


1533
VAL
N
5.865
56.984
22.375
14.24


1534
VAL
CA
5.933
57.538
23.723
13.51


1535
VAL
C
4.501
57.778
24.246
14.35


1536
VAL
O
3.562
57.882
23.459
15.05


1537
VAL
CB
6.733
58.845
23.784
11.74


1538
VAL
CG1
6.121
60.069
23.102
10.72


1539
VAL
CG2
8.255
58.752
23.835
12.09


1540
PRO
N
4.336
57.872
25.595
15.06


1541
PRO
CA
3.040
58.236
26.137
16.11


1542
PRO
C
2.530
59.619
25.634
17.94


1543
PRO
O
3.317
60.468
25.242
18.05


1544
PRO
CB
3.302
58.226
27.645
13.63


1545
PRO
CG
4.528
57.385
27.893
12.41


1546
PRO
CD
5.346
57.630
26.643
13.69


1547
GLU
N
1.202
59.808
25.668
20.58


1548
GLU
CA
0.652
61.098
25.215
24.47


1549
GLU
C
1.250
62.298
25.940
22.91


1550
GLU
O
1.492
63.361
25.390
25.20


1551
GLU
CB
−0.850
61.158
25.409
32.07


1552
GLU
CG
−1.590
60.311
24.379
47.45


1553
GLU
CD
−3.087
60.502
24.517
58.57


1554
GLU
OE1
−3.532
61.222
25.432
65.04


1555
GLU
OE2
−3.790
59.928
23.682
61.51


1556
SER
N
1.500
62.076
27.234
18.37


1557
SER
CA
2.197
63.131
27.944
15.28


1558
SER
C
2.757
62.537
29.222
14.24


1559
SER
O
2.365
61.449
29.650
14.09


1560
SER
CB
1.096
64.150
28.335
16.36


1561
SER
OG
−0.038
63.590
29.064
13.71


1562
PRO
N
3.694
63.279
29.870
16.15


1563
PRO
CA
4.138
62.933
31.224
15.80


1564
PRO
C
3.004
62.717
32.253
14.92


1565
PRO
O
3.058
61.827
33.071
16.83


1566
PRO
CB
5.050
64.111
31.635
15.53


1567
PRO
CG
5.523
64.712
30.308
13.98


1568
PRO
CD
4.387
64.458
29.311
14.91


1569
ALA
N
1.938
63.509
32.155
13.73


1570
ALA
CA
0.888
63.387
33.176
11.80


1571
ALA
C
0.126
62.067
33.107
12.67


1572
ALA
O
−0.162
61.442
34.116
15.33


1573
ALA
CB
−0.118
64.507
32.976
10.12


1574
SER
N
−0.196
61.656
31.875
13.30


1575
SER
CA
−0.925
60.382
31.746
13.82


1576
SER
C
−0.019
59.148
32.010
13.05


1577
SER
O
−0.412
58.220
32.690
15.15


1578
SER
CB
−1.429
60.366
30.317
14.32


1579
SER
OG
−0.511
60.907
29.312
19.74


1580
PHE
N
1.239
59.221
31.521
12.50


1581
PHE
CA
2.228
58.251
32.002
12.76


1582
PHE
C
2.343
58.176
33.577
11.82


1583
PHE
O
2.186
57.121
34.169
11.88


1584
PHE
CB
3.615
58.605
31.431
13.14


1585
PHE
CG
4.637
57.656
32.013
16.05


1586
PHE
CD1
4.686
56.327
31.585
14.24


1587
PHE
CD2
5.489
58.064
33.038
13.37


1588
PHE
CE1
5.556
55.424
32.196
13.11


1589
PHE
CE2
6.349
57.150
33.644
11.48


1590
PHE
CZ
6.383
55.827
33.237
9.34


1591
LEU
N
2.617
59.319
34.219
11.77


1592
LEU
CA
2.708
59.367
35.689
11.73


1593
LEU
C
1.410
58.893
36.391
10.70


1594
LEU
O
1.438
58.216
37.408
10.38


1595
LEU
CB
3.025
60.798
36.167
9.36


1596
LEU
CG
4.478
61.159
35.960
5.68


1597
LEU
CD1
5.549
60.306
36.660
9.00


1598
LEU
CD2
4.835
62.638
35.814
3.73


1599
ASN
N
0.271
59.271
35.828
10.41


1600
ASN
CA
−0.968
58.792
36.423
11.16


1601
ASN
C
−1.089
57.240
36.314
11.19


1602
ASN
O
−1.352
56.580
37.305
13.76


1603
ASN
CB
−2.069
59.596
35.747
11.22


1604
ASN
CG
−3.518
59.183
36.219
12.14


1605
ASN
OD1
−3.896
59.472
37.330
14.92


1606
ASN
ND2
−4.309
58.498
35.428
8.22


1607
PHE
N
−0.805
56.671
35.119
10.54


1608
PHE
CA
−0.779
55.193
35.030
10.34


1609
PHE
C
0.248
54.567
36.012
11.26


1610
PHE
O
−0.042
53.601
36.688
14.43


1611
PHE
CB
−0.512
54.781
33.582
10.28


1612
PHE
CG
−0.425
53.288
33.361
9.79


1613
PHE
CD1
0.808
52.629
33.406
11.60


1614
PHE
CD2
−1.556
52.540
33.059
9.63


1615
PHE
CE1
0.895
51.260
33.146
9.17


1616
PHE
CE2
−1.479
51.172
32.813
8.28


1617
PHE
CZ
−0.255
50.534
32.852
7.12


1618
LEU
N
1.439
55.168
36.111
11.04


1619
LEU
CA
2.470
54.642
36.987
9.37


1620
LEU
C
2.018
54.681
38.463
10.19


1621
LEU
O
2.198
53.743
39.237
10.47


1622
LEU
CB
3.736
55.476
36.727
8.63


1623
LEU
CG
4.917
55.081
37.636
6.66


1624
LEU
CD1
6.117
56.024
37.650
2.00


1625
LEU
CD2
5.215
53.570
37.847
4.01


1626
PHE
N
1.397
55.809
38.841
11.88


1627
PHE
CA
0.953
55.953
40.219
12.54


1628
PHE
C
−0.257
55.057
40.464
11.68


1629
PHE
O
−0.343
54.449
41.499
13.53


1630
PHE
CB
0.677
57.419
40.583
18.00


1631
PHE
CG
1.923
58.166
41.007
19.08


1632
PHE
CD1
3.029
58.239
40.174
19.03


1633
PHE
CD2
1.996
58.784
42.248
20.54


1634
PHE
CE1
4.208
58.855
40.582
18.32


1635
PHE
CE2
3.162
59.434
42.649
23.62


1636
PHE
CZ
4.284
59.461
41.825
21.78


1637
LYS
N
−1.164
54.891
39.512
11.07


1638
LYS
CA
−2.120
53.796
39.650
12.85


1639
LYS
C
−1.477
52.463
40.008
14.04


1640
LYS
O
−1.967
51.768
40.896
16.37


1641
LYS
CB
−2.922
53.586
38.373
16.95


1642
LYS
CG
−4.318
54.180
38.510
21.62


1643
LYS
CD
−5.385
53.142
38.905
25.54


1644
LYS
CE
−6.673
53.761
39.500
25.67


1645
LYS
NZ
−7.774
52.779
39.478
30.26


1646
VAL
N
−0.356
52.121
39.336
14.89


1647
VAL
CA
0.251
50.822
39.694
14.57


1648
VAL
C
0.969
50.877
41.070
14.27


1649
VAL
O
0.927
49.926
41.836
14.66


1650
VAL
CB
1.287
50.408
38.602
12.16


1651
VAL
CG1
0.967
50.623
37.128
10.83


1652
VAL
CG2
2.179
49.194
38.894
11.91


1653
ARG
N
1.645
52.008
41.379
14.32


1654
ARG
CA
2.136
52.229
42.754
15.07


1655
ARG
C
1.031
52.174
43.854
14.33


1656
ARG
O
1.086
51.389
44.780
14.82


1657
ARG
CB
2.852
53.578
42.830
17.02


1658
ARG
CG
4.273
53.559
42.279
13.14


1659
ARG
CD
4.819
54.963
42.208
14.56


1660
ARG
NE
6.213
54.951
41.816
17.25


1661
ARG
CZ
7.151
55.597
42.478
14.40


1662
ARG
NH1
6.810
56.358
43.478
11.54


1663
ARG
NH2
8.404
55.427
42.163
14.05


1664
GLU
N
0.019
52.995
43.747
13.57


1665
GLU
CA
−1.064
52.972
44.716
15.15


1666
GLU
C
−1.655
51.587
44.982
15.15


1667
GLU
O
−2.117
51.259
46.064
17.25


1668
GLU
CB
−2.186
53.776
44.127
17.33


1669
GLU
CG
−1.783
55.240
44.116
26.73


1670
GLU
CD
−2.040
55.944
45.433
33.32


1671
GLU
OE1
−1.492
57.025
45.592
34.31


1672
GLU
OE2
−2.768
55.425
46.287
38.92


1673
SER
N
−1.601
50.783
43.914
15.09


1674
SER
CA
−2.190
49.461
43.984
15.03


1675
SER
C
−1.471
48.479
44.930
16.60


1676
SER
O
−1.954
47.372
45.132
19.63


1677
SER
CB
−2.078
48.789
42.605
13.60


1678
SER
OG
−0.807
48.101
42.352
12.81


1679
GLY
N
−0.289
48.848
45.456
16.76


1680
GLY
CA
0.383
47.836
46.262
17.69


1681
GLY
C
1.256
46.857
45.477
21.84


1682
GLY
O
2.059
46.140
46.045
25.25


1683
SER
N
1.187
46.859
44.143
21.52


1684
SER
CA
1.899
45.727
43.512
18.70


1685
SER
C
3.343
45.801
43.485
21.56


1686
SER
O
3.983
44.799
43.241
23.22


1687
SER
CB
1.526
45.671
41.996
17.25


1688
SER
OG
0.078
45.551
41.812
15.02


1689
LEU
N
3.832
47.043
43.689
22.71


1690
LEU
CA
5.267
47.260
43.621
25.21


1691
LEU
C
5.971
46.987
44.956
28.44


1692
LEU
O
7.168
47.166
45.123
32.40


1693
LEU
CB
5.530
48.678
43.103
23.08


1694
LEU
CG
5.152
48.831
41.627
22.44


1695
LEU
CD1
6.028
47.953
40.742
22.73


1696
LEU
CD2
5.302
50.276
41.155
22.80


1697
SER
N
5.140
46.673
45.939
30.11


1698
SER
CA
5.719
46.649
47.256
33.16


1699
SER
C
6.475
45.373
47.510
31.90


1700
SER
O
6.234
44.343
46.911
34.68


1701
SER
CB
4.546
46.921
48.203
37.54


1702
SER
OG
4.262
48.388
48.292
42.64


1703
PRO
N
7.461
45.477
48.448
28.58


1704
PRO
CA
8.460
44.430
48.554
26.29


1705
PRO
C
7.977
43.176
49.267
25.94


1706
PRO
O
8.685
42.192
49.313
25.90


1707
PRO
CB
9.540
45.047
49.415
25.82


1708
PRO
CG
8.802
46.052
50.292
27.01


1709
PRO
CD
7.625
46.520
49.442
26.00


1710
GLU
N
6.753
43.231
49.826
25.30


1711
GLU
CA
6.147
41.998
50.313
25.00


1712
GLU
C
5.678
41.030
49.167
23.01


1713
GLU
O
5.322
39.874
49.383
23.82


1714
GLU
CB
5.055
42.375
51.309
32.49


1715
GLU
CG
4.100
43.491
50.809
45.13


1716
GLU
CD
2.635
43.121
51.003
53.12


1717
GLU
OE1
2.305
41.954
51.249
57.67


1718
GLU
OE2
1.825
44.041
50.923
54.61


1719
HIS
N
5.757
41.530
47.916
19.60


1720
HIS
CA
5.382
40.713
46.750
16.53


1721
HIS
C
6.608
40.318
45.908
14.85


1722
HIS
O
7.657
40.935
46.002
18.13


1723
HIS
CB
4.469
41.549
45.834
16.49


1724
HIS
CG
3.186
41.819
46.543
16.48


1725
HIS
ND1
2.705
43.052
46.753
19.82


1726
HIS
CD2
2.315
40.880
47.113
17.11


1727
HIS
CE1
1.564
42.877
47.445
17.32


1728
HIS
NE2
1.308
41.580
47.657
16.80


1729
GLY
N
6.441
39.313
45.037
10.74


1730
GLY
CA
7.480
39.072
44.033
8.36


1731
GLY
C
7.639
40.271
43.101
10.21


1732
GLY
O
6.842
41.204
43.135
10.12


1733
PRO
N
8.672
40.305
42.215
11.23


1734
PRO
CA
8.791
41.488
41.376
11.31


1735
PRO
C
7.586
41.597
40.436
13.76


1736
PRO
O
7.115
40.556
39.982
15.58


1737
PRO
CB
10.071
41.270
40.602
11.62


1738
PRO
CG
10.485
39.825
40.768
10.97


1739
PRO
CD
9.655
39.266
41.909
10.99


1740
VAL
N
7.067
42.823
40.180
12.46


1741
VAL
CA
6.099
43.008
39.084
10.53


1742
VAL
C
6.698
42.540
37.776
8.69


1743
VAL
O
7.876
42.742
37.532
5.62


1744
VAL
CB
5.714
44.493
39.007
12.64


1745
VAL
CG1
4.325
44.836
38.477
13.13


1746
VAL
CG2
6.817
45.499
38.640
14.34


1747
VAL
N
5.857
41.916
36.948
8.33


1748
VAL
CA
6.266
41.620
35.592
10.28


1749
VAL
C
5.777
42.727
34.650
10.89


1750
VAL
O
4.589
42.975
34.553
14.16


1751
VAL
CB
5.588
40.298
35.212
7.81


1752
VAL
CG1
5.790
39.085
36.150
3.89


1753
VAL
CG2
5.488
39.993
33.708
9.30


1754
VAL
N
6.693
43.374
33.943
8.73


1755
VAL
CA
6.230
44.364
32.984
8.66


1756
VAL
C
6.557
43.846
31.596
11.40


1757
VAL
O
7.631
43.296
31.372
11.10


1758
VAL
CB
7.079
45.597
33.283
4.62


1759
VAL
CG1
7.273
45.981
34.747
5.26


1760
VAL
CG2
7.039
46.751
32.271
6.18


1761
HIS
N
5.625
44.053
30.653
11.47


1762
HIS
CA
5.949
43.726
29.291
9.12


1763
HIS
C
5.390
44.767
28.325
10.76


1764
HIS
O
4.416
45.484
28.572
9.76


1765
HIS
CB
5.537
42.311
28.991
7.01


1766
HIS
CG
4.100
42.188
28.648
6.87


1767
HIS
ND1
3.610
42.276
27.377
6.42


1768
HIS
CD2
3.046
41.886
29.498
7.35


1769
HIS
CE1
2.317
42.030
27.445
3.34


1770
HIS
NE2
1.946
41.795
28.713
6.66


1771
CYS
N
6.034
44.779
27.145
9.68


1772
CYS
CA
5.396
45.284
25.959
8.47


1773
CYS
C
5.349
44.168
24.910
8.61


1774
CYS
O
5.015
43.037
25.183
9.39


1775
CYS
CB
6.155
46.470
25.439
9.17


1776
CYS
SG
7.918
46.279
25.682
10.04


1777
SER
N
5.732
44.480
23.683
8.84


1778
SER
CA
5.746
43.399
22.743
8.32


1779
SER
C
7.091
42.628
22.814
9.11


1780
SER
O
7.164
41.412
22.865
6.41


1781
SER
CB
5.589
44.028
21.316
4.93


1782
SER
OG
5.503
43.095
20.188
2.00


1783
ALA
N
8.209
43.407
22.865
8.74


1784
ALA
CA
9.538
42.795
23.004
5.14


1785
ALA
C
9.982
42.703
24.478
8.48


1786
ALA
O
10.901
41.977
24.865
8.15


1787
ALA
CB
10.555
43.604
22.223
2.07


1788
GLY
N
9.283
43.536
25.298
7.00


1789
GLY
CA
9.738
43.634
26.670
7.25


1790
GLY
C
10.994
44.521
26.895
9.02


1791
GLY
O
11.684
44.322
27.873
8.42


1792
ILE
N
11.272
45.454
25.949
8.13


1793
ILE
CA
12.439
46.358
26.075
6.90


1794
ILE
C
12.129
47.884
25.909
6.67


1795
ILE
O
12.517
48.706
26.735
6.93


1796
ILE
CB
13.600
45.878
25.157
7.40


1797
ILE
CG1
13.304
45.896
23.645
6.63


1798
ILE
CG2
14.029
44.484
25.566
6.11


1799
ILE
CD1
14.447
45.330
22.799
2.00


1800
GLY
N
11.389
48.259
24.844
5.07


1801
GLY
CA
11.257
49.697
24.559
3.39


1802
GLY
C
10.479
50.506
25.591
7.26


1803
GLY
O
11.016
51.213
26.448
8.47


1804
ARG
N
9.146
50.302
25.486
9.36


1805
ARG
CA
8.119
50.783
26.438
7.15


1806
ARG
C
8.349
50.290
27.911
8.03


1807
ARG
O
8.254
51.041
28.878
5.27


1808
ARG
CB
6.735
50.387
25.888
4.52


1809
ARG
CG
6.355
51.122
24.594
7.50


1810
ARG
CD
4.963
50.741
24.037
5.39


1811
ARG
NE
5.123
49.454
23.386
2.97


1812
ARG
CZ
4.249
48.999
22.515
6.48


1813
ARG
NH1
3.100
49.567
22.403
8.00


1814
ARG
NH2
4.539
48.025
21.692
6.37


1815
SER
N
8.704
48.990
28.053
8.64


1816
SER
CA
8.988
48.505
29.429
11.85


1817
SER
C
10.194
49.159
30.098
13.94


1818
SER
O
10.135
49.549
31.256
14.70


1819
SER
CB
9.251
46.983
29.317
9.42


1820
SER
OG
8.298
46.180
28.561
10.50


1821
GLY
N
11.295
49.287
29.298
13.08


1822
GLY
CA
12.465
50.017
29.805
12.72


1823
GLY
C
12.183
51.482
30.203
12.38


1824
GLY
O
12.630
51.952
31.232
11.48


1825
THR
N
11.373
52.164
29.392
13.33


1826
THR
CA
10.876
53.522
29.710
12.47


1827
THR
C
10.128
53.607
31.051
11.44


1828
THR
O
10.480
54.379
31.932
10.01


1829
THR
CB
9.919
53.908
28.580
13.96


1830
THR
OG1
10.500
53.936
27.312
14.77


1831
THR
CG2
9.296
55.291
28.720
14.36


1832
PHE
N
9.086
52.761
31.159
10.63


1833
PHE
CA
8.301
52.618
32.390
10.77


1834
PHE
C
9.161
52.415
33.683
13.07


1835
PHE
O
9.077
53.163
34.662
13.04


1836
PHE
CB
7.336
51.445
32.182
7.40


1837
PHE
CG
6.474
51.211
33.370
8.91


1838
PHE
CD1
5.294
51.939
33.535
9.56


1839
PHE
CD2
6.833
50.260
34.332
11.15


1840
PHE
CE1
4.472
51.724
34.635
6.80


1841
PHE
CE2
6.011
50.042
35.441
12.86


1842
PHE
CZ
4.826
50.776
35.585
8.20


1843
CYS
N
10.001
51.358
33.587
11.48


1844
CYS
CA
10.913
51.025
34.674
11.25


1845
CYS
C
11.955
52.098
34.908
10.61


1846
CYS
O
12.298
52.389
36.041
11.12


1847
CYS
CB
11.666
49.694
34.478
12.63


1848
CYS
SG
10.535
48.313
34.271
13.23


1849
LEU
N
12.490
52.692
33.840
7.85


1850
LEU
CA
13.512
53.666
34.153
7.84


1851
LEU
C
12.924
54.861
34.963
9.98


1852
LEU
O
13.454
55.271
36.001
9.91


1853
LEU
CB
14.179
54.130
32.867
8.17


1854
LEU
CG
15.152
55.294
33.101
8.10


1855
LEU
CD1
15.641
55.866
31.788
10.22


1856
LEU
CD2
16.308
54.805
33.900
5.46


1857
ALA
N
11.765
55.366
34.479
9.15


1858
ALA
CA
11.145
56.409
35.272
8.72


1859
ALA
C
10.859
55.961
36.758
9.37


1860
ALA
O
11.252
56.616
37.720
8.82


1861
ALA
CB
9.933
56.906
34.502
6.08


1862
ASP
N
10.206
54.798
36.899
12.15


1863
ASP
CA
9.882
54.384
38.274
12.54


1864
ASP
C
11.120
54.327
39.195
12.62


1865
ASP
O
11.125
54.868
40.301
14.12


1866
ASP
CB
9.135
53.047
38.255
10.97


1867
ASP
CG
8.677
52.635
39.683
13.96


1868
ASP
OD1
8.123
53.446
40.424
11.13


1869
ASP
OD2
8.896
51.507
40.090
16.12


1870
THR
N
12.183
53.716
38.673
11.33


1871
THR
CA
13.409
53.627
39.496
12.31


1872
THR
C
14.030
54.924
39.818
12.62


1873
THR
O
14.421
55.178
40.946
13.17


1874
THR
CB
14.390
52.694
38.719
12.56


1875
THR
OG1
13.877
51.364
38.413
12.72


1876
THR
CG2
15.640
52.493
39.580
10.83


1877
CYS
N
14.069
55.784
38.801
11.92


1878
CYS
GA
14.552
57.116
39.077
10.93


1879
CYS
C
13.771
57.825
40.199
11.91


1880
CYS
O
14.365
58.424
41.096
13.19


1881
CYS
CB
14.542
57.925
37.797
10.56


1882
CYS
SG
15.955
57.393
36.809
11.98


1883
LEU
N
12.437
57.700
40.148
10.59


1884
LEU
CA
11.638
58.318
41.208
11.97


1885
LEU
C
11.860
57.690
42.599
12.62


1886
LEU
O
12.008
58.369
43.598
16.19


1887
LEU
CB
10.156
58.266
40.800
11.83


1888
LEU
CG
9.808
59.325
39.729
7.13


1889
LEU
CD1
10.407
60.753
39.850
6.19


1890
LEU
CD2
8.408
59.256
39.129
7.45


1891
LEU
N
11.933
56.374
42.599
10.74


1892
LEU
GA
12.298
55.683
43.835
12.52


1893
LEU
C
13.630
56.165
44.485
14.94


1894
LEU
O
13.753
56.451
45.664
14.86


1895
LEU
CB
12.445
54.210
43.454
14.62


1896
LEU
CG
12.070
53.202
44.542
18.58


1897
LEU
CD1
11.573
53.687
45.902
18.58


1898
LEU
CD2
12.714
51.819
44.495
18.21


1899
LEU
N
14.657
56.205
43.622
16.93


1900
LEU
CA
15.944
56.730
44.029
16.68


1901
LEU
C
15.899
58.125
44.634
17.07


1902
LEU
O
16.407
58.365
45.718
17.96


1903
LEU
CB
16.865
56.799
42.823
15.86


1904
LEU
CG
17.819
55.637
42.653
16.83


1905
LEU
CD1
18.150
55.210
41.239
20.58


1906
LEU
CD2
17.889
54.560
43.724
20.85


1907
MET
N
15.289
59.030
43.862
17.43


1908
MET
CA
15.045
60.372
44.363
17.74


1909
MET
C
14.356
60.343
45.749
20.59


1910
MET
O
14.705
61.087
46.653
19.57


1911
MET
CB
14.202
61.069
43.311
15.42


1912
MET
CG
14.045
62.573
43.556
22.27


1913
MET
SD
13.221
63.451
42.216
26.88


1914
MET
CE
14.257
62.910
40.846
20.89


1915
ASP
N
13.406
59.399
45.879
21.94


1916
ASP
CA
12.588
59.263
47.068
20.62


1917
ASP
C
13.373
58.964
48.367
22.12


1918
ASP
O
13.158
59.545
49.428
21.16


1919
ASP
CB
11.560
58.168
46.825
17.54


1920
ASP
CG
10.247
58.505
47.525
17.97


1921
ASP
OD1
10.130
59.552
48.186
16.33


1922
ASP
OD2
9.323
57.702
47.398
16.58


1923
LYS
N
14.304
58.014
48.244
24.18


1924
LYS
CA
14.838
57.506
49.461
30.25


1925
LYS
C
15.855
58.477
50.159
31.26


1926
LYS
O
16.111
58.474
51.360
31.16


1927
LYS
CB
15.431
56.139
49.330
34.06


1928
LYS
CG
16.631
56.140
48.175
37.83


1929
LYS
CD
16.505
54.826
47.413
40.81


1930
LYS
CE
15.165
53.967
47.642
45.68


1931
LYS
NZ
15.491
52.600
48.093
49.67


1932
ARG
N
16.448
59.284
49.291
32.87


1933
ARG
CA
17.298
60.331
49.838
34.54


1934
ARG
C
16.556
61.652
49.897
32.47


1935
ARG
O
16.969
62.544
50.607
35.59


1936
ARG
CB
18.529
60.438
48.950
40.97


1937
ARG
CG
18.224
60.378
47.464
42.29


1938
ARG
CD
19.440
59.951
46.685
46.58


1939
ARG
NE
19.789
58.566
46.787
51.13


1940
ARG
CZ
20.305
57.917
45.732
51.55


1941
ARG
NH1
20.573
58.530
44.593
50.19


1942
ARG
NH2
20.556
56.659
45.871
52.57


1943
LYS
N
15.477
61.744
49.085
28.06


1944
LYS
CA
14.887
63.034
48.739
23.26


1945
LYS
C
15.871
63.979
48.006
22.95


1946
LYS
O
15.846
65.185
48.145
24.32


1947
LYS
CB
14.280
63.666
49.994
20.64


1948
LYS
CG
13.096
62.885
50.574
17.75


1949
LYS
CD
11.829
63.028
49.746
16.37


1950
LYS
CE
10.610
62.496
50.484
18.59


1951
LYS
NZ
9.607
61.996
49.547
18.19


1952
ASP
N
16.744
63.378
47.216
22.49


1953
ASP
CA
17.804
64.139
46.613
22.01


1954
ASP
C
17.837
63.901
45.057
22.36


1955
ASP
O
18.396
63.068
44.529
20.34


1956
ASP
CB
19.135
63.784
47.280
22.14


1957
ASP
CG
20.281
64.530
46.551
24.82


1958
ASP
OD1
20.036
65.282
45.596
27.44


1959
ASP
OD2
21.408
64.386
46.894
28.31


1960
PRO
N
17.129
64.817
44.351
22.38


1961
PRO
CA
17.082
64.625
42.912
22.74


1962
PRO
C
18.394
64.663
42.163
23.45


1963
PRO
O
18.563
64.065
41.106
23.06


1964
PRO
CB
16.208
65.798
42.474
22.60


1965
PRO
CG
15.495
66.302
43.723
20.02


1966
PRO
CD
16.375
65.912
44.883
22.19


1967
SER
N
19.308
65.388
42.820
25.88


1968
SER
CA
20.553
65.744
42.163
28.66


1969
SER
C
21.583
64.640
42.365
28.70


1970
SER
O
22.595
64.553
41.674
34.40


1971
SER
CB
20.987
67.189
42.600
32.17


1972
SER
OG
20.078
68.376
42.408
38.47


1973
SER
N
21.286
63.704
43.228
24.95


1974
SER
CA
22.122
62.506
43.080
22.47


1975
SER
C
21.408
61.415
42.208
24.29


1976
SER
O
21.632
60.237
42.481
28.47


1977
SER
CB
21.899
61.880
44.476
19.35


1978
SER
OG
20.447
61.522
44.588
19.02


1979
VAL
N
20.496
61.724
41.238
23.38


1980
VAL
CA
20.110
60.629
40.317
21.74


1981
VAL
C
20.696
60.973
38.944
21.15


1982
VAL
O
20.505
62.041
38.378
21.56


1983
VAL
CB
18.614
60.127
40.291
22.27


1984
VAL
CG1
17.992
60.001
38.888
19.64


1985
VAL
CG2
17.642
60.735
41.319
19.29


1986
ASP
N
21.402
60.004
38.419
19.17


1987
ASP
CA
21.900
60.033
37.078
18.10


1988
ASP
C
21.109
59.025
36.194
15.54


1989
ASP
O
21.381
57.837
36.153
15.08


1990
ASP
CB
23.343
59.668
37.302
19.38


1991
ASP
CG
24.180
59.829
36.067
22.12


1992
ASP
OD1
23.681
59.769
34.927
18.04


1993
ASP
OD2
25.375
60.010
36.276
24.29


1994
ILE
N
20.110
59.581
35.484
15.98


1995
ILE
CA
19.186
58.824
34.619
14.13


1996
ILE
C
19.943
57.927
33.639
13.36


1997
ILE
O
19.658
56.735
33.541
14.33


1998
ILE
CB
18.150
59.751
33.905
14.98


1999
ILE
CG1
17.376
60.610
34.912
15.47


2000
ILE
CG2
17.135
58.986
33.014
15.21


2001
ILE
CD1
16.406
61.621
34.258
15.57


2002
LYS
N
20.940
58.512
32.906
13.55


2003
LYS
CA
21.574
57.679
31.868
14.54


2004
LYS
C
22.324
56.502
32.481
12.60


2005
LYS
O
22.324
55.397
31.976
14.35


2006
LYS
CB
22.600
58.431
31.039
19.78


2007
LYS
CG
22.050
59.595
30.233
28.21


2008
LYS
CD
23.189
60.536
29.694
33.36


2009
LYS
CE
24.131
61.030
30.806
38.77


2010
LYS
NZ
24.213
62.457
30.838
39.28


2011
LYS
N
22.936
56.831
33.609
13.28


2012
LYS
CA
23.649
55.839
34.394
15.81


2013
LYS
C
22.728
54.716
34.947
16.74


2014
LYS
O
23.120
53.553
35.015
17.00


2015
LYS
CB
24.324
56.596
35.524
18.25


2016
LYS
CG
25.428
55.816
36.190
24.61


2017
LYS
CD
26.426
56.748
36.886
31.08


2018
LYS
CE
27.219
57.609
35.891
33.12


2019
LYS
NZ
28.384
58.196
36.565
38.51


2020
VAL
N
21.473
55.107
35.320
15.03


2021
VAL
CA
20.508
54.123
35.787
12.06


2022
VAL
C
19.952
53.242
34.667
10.81


2023
VAL
O
19.752
52.042
34.805
10.34


2024
VAL
CB
19.461
54.608
36.785
11.58


2025
VAL
CG1
18.054
54.087
36.638
10.48


2026
VAL
CG2
19.699
55.895
37.544
10.22


2027
LEU
N
19.772
53.885
33.526
10.79


2028
LEU
CA
19.436
53.099
32.349
8.94


2029
LEU
C
20.548
52.062
32.020
8.48


2030
LEU
O
20.294
50.918
31.723
8.83


2031
LEU
CB
19.293
54.082
31.185
10.94


2032
LEU
CG
18.735
53.416
29.924
12.07


2033
LEU
CD1
18.531
54.306
28.709
12.15


2034
LEU
CD2
17.687
52.271
30.071
12.74


2035
LEU
N
21.797
52.491
32.138
8.39


2036
LEU
CA
22.910
51.562
31.944
9.03


2037
LEU
C
23.023
50.436
33.014
9.12


2038
LEU
O
23.321
49.296
32.672
11.52


2039
LEU
CB
24.196
52.402
31.926
12.18


2040
LEU
CG
24.764
52.758
30.531
14.87


2041
LEU
CD1
25.445
54.117
30.349
13.96


2042
LEU
CD2
24.118
52.171
29.284
16.58


2043
ASP
N
22.759
50.740
34.317
10.70


2044
ASP
CA
22.692
49.615
35.266
12.69


2045
ASP
C
21.562
48.644
34.854
12.49


2046
ASP
O
21.672
47.428
34.883
13.96


2047
ASP
CB
22.578
50.077
36.745
12.75


2048
ASP
CG
23.504
49.125
37.609
19.37


2049
ASP
OD1
24.668
49.405
37.774
18.61


2050
ASP
OD2
23.102
48.048
38.058
18.50


2051
MET
N
20.479
49.260
34.346
13.94


2052
MET
CA
19.382
48.416
33.885
12.52


2053
MET
C
19.769
47.475
32.725
11.34


2054
MET
O
19.403
46.298
32.750
10.85


2055
MET
CB
18.218
49.297
33.477
12.33


2056
MET
CG
17.250
49.543
34.624
15.57


2057
MET
SD
15.727
50.299
34.084
17.56


2058
MET
CE
15.056
50.546
35.719
21.12


2059
ARG
N
20.500
48.014
31.717
10.37


2060
ARG
CA
20.829
47.189
30.532
11.63


2061
ARG
C
21.931
46.116
30.833
12.35


2062
ARG
O
22.276
45.276
30.016
14.86


2063
ARG
CB
21.135
48.021
29.251
7.82


2064
ARG
CG
20.382
49.348
29.129
10.04


2065
ARG
CD
19.630
49.616
27.841
10.30


2066
ARG
NE
20.491
49.785
26.689
13.76


2067
ARG
CZ
20.030
50.198
25.490
13.60


2068
ARG
NH1
18.843
50.675
25.351
14.69


2069
ARG
NH2
20.742
50.080
24.428
14.13


2070
LYS
N
22.428
46.114
32.087
9.97


2071
LYS
CA
23.169
44.943
32.556
9.28


2072
LYS
C
22.295
43.656
32.712
10.67


2073
LYS
O
22.771
42.535
32.720
11.47


2074
LYS
CB
23.764
45.238
33.939
10.01


2075
LYS
CG
24.737
46.407
33.949
8.63


2076
LYS
CD
25.212
46.730
35.354
11.76


2077
LYS
CE
26.300
47.806
35.387
8.10


2078
LYS
NZ
26.725
47.986
36.771
8.13


2079
PHE
N
20.978
43.866
32.874
9.59


2080
PHE
CA
20.099
42.748
33.170
6.82


2081
PHE
C
19.223
42.333
31.987
7.73


2082
PHE
O
18.813
41.194
31.885
9.01


2083
PHE
CB
19.214
43.172
34.302
7.16


2084
PHE
CG
20.005
43.498
35.521
6.83


2085
PHE
CD1
20.451
42.470
36.348
11.66


2086
PHE
CD2
20.290
44.810
35.847
7.67


2087
PHE
CE1
21.108
42.746
37.544
9.99


2088
PHE
CE2
20.987
45.098
37.012
9.82


2089
PHE
CZ
21.389
44.069
37.871
10.60


2090
ARG
N
18.928
43.295
31.101
6.54


2091
ARG
CA
18.312
42.935
29.815
5.34


2092
ARG
C
18.778
43.936
28.745
6.76


2093
ARG
O
18.946
45.121
29.033
6.23


2094
ARG
CB
16.793
42.959
29.957
6.13


2095
ARG
CG
16.003
42.371
28.786
4.01


2096
ARG
CD
14.522
42.202
29.163
6.42


2097
ARG
NE
13.698
41.832
28.004
7.85


2098
ARG
CZ
13.475
40.588
27.608
7.40


2099
ARG
NH1
14.082
39.611
28.213
5.55


2100
ARG
NH2
12.650
40.317
26.626
8.19


2101
MET
N
18.984
43.449
27.517
6.50


2102
MET
CA
19.373
44.300
26.373
5.07


2103
MET
C
18.264
45.269
25.893
4.52


2104
MET
O
17.077
45.011
25.922
5.43


2105
MET
CB
19.754
43.386
25.208
5.61


2106
MET
CG
18.602
42.498
24.719
8.08


2107
MET
SD
19.100
41.534
23.260
10.26


2108
MET
CE
20.352
40.481
24.035
6.83


2109
GLY
N
18.702
46.408
25.380
5.33


2110
GLY
CA
17.798
47.158
24.511
6.72


2111
GLY
C
16.765
48.002
25.246
7.88


2112
GLY
O
15.895
48.607
24.644
8.44


2113
LEU
N
16.917
48.057
26.575
7.79


2114
LEU
CA
15.991
48.835
27.389
7.90


2115
LEU
C
15.847
50.280
26.931
9.43


2116
LEU
O
16.811
51.025
26.952
11.69


2117
LEU
CB
16.435
48.759
28.855
5.63


2118
LEU
CG
16.114
47.411
29.485
3.21


2119
LEU
CD1
14.875
46.664
28.964
2.00


2120
LEU
CD2
16.413
47.234
30.993
6.08


2121
ILE
N
14.635
50.617
26.473
8.21


2122
ILE
CA
14.424
51.874
25.755
8.00


2123
ILE
C
15.014
51.906
24.344
9.79


2124
ILE
O
16.216
51.821
24.151
9.69


2125
ILE
CB
14.907
53.103
26.533
7.76


2126
ILE
CG1
14.427
53.121
27.981
5.80


2127
ILE
CG2
14.511
54.386
25.776
8.24


2128
ILE
CD1
14.710
54.364
28.762
7.02


2129
GLN
N
14.092
52.024
23.368
10.99


2130
GLN
CA
14.319
51.678
21.966
11.79


2131
GLN
C
14.653
52.880
21.069
11.05


2132
GLN
O
15.337
52.751
20.058
11.93


2133
GLN
CB
13.190
50.852
21.454
13.66


2134
GLN
CG
13.408
49.365
21.794
17.35


2135
GLN
CD
14.613
48.766
21.039
17.85


2136
GLN
OE1
14.671
48.808
19.824
17.92


2137
GLN
NE2
15.638
48.402
21.798
14.72


2138
THR
N
14.146
54.045
21.454
10.48


2139
THR
CA
14.523
55.241
20.676
10.99


2140
THR
C
15.015
56.439
21.584
10.88


2141
THR
O
14.872
56.440
22.812
13.32


2142
THR
CB
13.206
55.801
20.036
10.39


2143
THR
OG1
12.406
56.499
21.045
11.13


2144
THR
CG2
12.332
54.665
19.508
5.92


2145
ALA
N
15.526
57.490
20.947
11.27


2146
ALA
CA
16.040
58.653
21.696
12.40


2147
ALA
C
14.922
59.563
22.293
12.72


2148
ALA
O
15.128
60.317
23.230
12.68


2149
ALA
CB
16.884
59.495
20.743
9.84


2150
ASP
N
13.739
59.440
21.699
13.07


2151
ASP
CA
12.627
60.217
22.243
13.49


2152
ASP
C
11.999
59.518
23.460
11.38


2153
ASP
O
11.668
60.167
24.429
11.43


2154
ASP
CB
11.563
60.373
21.157
14.90


2155
ASP
CG
10.713
61.587
21.478
15.65


2156
ASP
OD1
11.277
62.628
21.814
20.35


2157
ASP
OD2
9.504
61.478
21.405
15.09


2158
GLN
N
11.911
58.184
23.464
8.92


2159
GLN
CA
11.597
57.530
24.722
9.07


2160
GLN
C
12.604
57.887
25.843
9.83


2161
GLN
O
12.229
58.053
26.996
11.31


2162
GLN
CB
11.618
56.017
24.539
6.40


2163
GLN
CG
10.410
55.426
23.789
7.52


2164
GLN
CD
10.618
53.949
23.490
8.30


2165
GLN
OE1
11.688
53.402
23.681
10.49


2166
GLN
NE2
9.596
53.335
22.960
5.63


2167
LEU
N
13.876
58.036
25.429
10.38


2168
LEU
CA
14.899
58.532
26.365
9.22


2169
LEU
C
14.542
59.919
26.917
11.76


2170
LEU
O
14.608
60.227
28.096
14.48


2171
LEU
CB
16.257
58.651
25.674
5.69


2172
LEU
CG
17.350
58.976
26.691
3.16


2173
LEU
CD1
18.730
59.387
26.183
3.34


2174
LEU
CD2
17.399
58.164
27.984
6.48


2175
ARG
N
14.189
60.765
25.959
11.77


2176
ARG
CA
13.847
62.121
26.325
11.99


2177
ARG
C
12.535
62.202
27.128
12.66


2178
ARG
O
12.373
63.015
28.034
15.67


2179
ARG
CB
13.757
62.891
25.023
10.45


2180
ARG
CG
13.274
64.311
25.258
11.84


2181
ARG
CD
12.982
64.996
23.947
14.66


2182
ARG
NE
12.991
66.432
24.187
15.50


2183
ARG
CZ
11.861
67.087
24.321
13.39


2184
ARG
NH1
10.719
66.475
24.238
14.80


2185
ARG
NH2
11.867
68.349
24.532
9.72


2186
PHE
N
11.590
61.331
26.796
10.85


2187
PHE
CA
10.374
61.254
27.565
10.59


2188
PHE
C
10.713
60.835
28.993
9.21


2189
PHE
O
10.219
61.439
29.914
13.15


2190
PHE
CB
9.413
60.250
26.930
12.58


2191
PHE
CG
8.132
60.221
27.703
13.60


2192
PHE
CD1
7.110
61.104
27.388
14.76


2193
PHE
CD2
7.968
59.339
28.773
15.39


2194
PHE
CE1
5.934
61.118
28.132
14.58


2195
PHE
CE2
6.799
59.362
29.523
15.49


2196
PHE
CZ
5.785
60.254
29.206
13.29


2197
SER
N
11.598
59.856
29.173
9.61


2198
SER
CA
12.076
59.508
30.549
11.91


2199
SER
C
12.490
60.695
31.440
13.91


2200
SER
O
12.041
60.822
32.561
15.55


2201
SER
CB
13.309
58.607
30.361
9.99


2202
SER
OG
12.988
57.388
29.633
13.54


2203
TYR
N
13.369
61.576
30.916
12.72


2204
TYR
CA
13.660
62.827
31.602
13.18


2205
TYR
C
12.385
63.670
31.910
14.92


2206
TYR
O
12.138
64.043
33.043
17.21


2207
TYR
CB
14.553
63.660
30.712
13.16


2208
TYR
CG
16.002
63.282
30.776
14.18


2209
TYR
CD1
16.411
62.111
30.180
16.94


2210
TYR
CD2
16.947
64.100
31.406
15.60


2211
TYR
CE1
17.734
61.726
30.172
18.68


2212
TYR
CE2
18.295
63.765
31.403
16.96


2213
TYR
CZ
18.682
62.574
30.758
19.92


2214
TYR
OH
20.008
62.233
30.655
20.96


2215
LEU
N
11.559
63.956
30.883
14.29


2216
LEU
CA
10.249
64.563
31.141
11.73


2217
LEU
C
9.468
63.942
32.331
13.72


2218
LEU
O
9.041
64.636
33.258
13.88


2219
LEU
CB
9.443
64.482
29.866
11.89


2220
LEU
CG
9.673
65.629
28.871
15.00


2221
LEU
CD1
9.334
65.412
27.398
15.00


2222
LEU
CD2
10.774
66.642
29.158
14.31


2223
ALA
N
9.318
62.599
32.273
13.35


2224
ALA
CA
8.564
61.864
33.295
12.89


2225
ALA
C
9.213
62.040
34.696
13.12


2226
ALA
O
8.582
62.474
35.653
13.73


2227
ALA
CB
8.309
60.393
32.891
10.58


2228
VAL
N
10.503
61.743
34.779
11.11


2229
VAL
CA
11.204
61.933
36.054
10.33


2230
VAL
C
11.237
63.384
36.609
10.96


2231
VAL
O
10.993
63.608
37.784
12.23


2232
VAL
CB
12.606
61.377
35.913
10.20


2233
VAL
CG1
12.546
59.906
35.484
11.84


2234
VAL
CG2
13.332
61.458
37.253
10.96


2235
ILE
N
11.560
64.377
35.760
10.85


2236
ILE
CA
11.577
65.764
36.191
8.53


2237
ILE
C
10.208
66.186
36.747
9.55


2238
ILE
O
10.125
66.781
37.812
13.70


2239
ILE
CB
12.040
66.687
35.033
12.52


2240
ILE
CG1
13.570
66.56
434.80
611.25


2241
ILE
CG2
11.699
68.16
435.33
53.61


2242
ILE
CD1
14.012
67.08
733.435
12.56


2243
GLU
N
9.121
65.820
36.020
9.61


2244
GLU
CA
7.751
66.097
36.515
9.71


2245
GLU
C
7.388
65.403
37.845
11.33


2246
GLU
O
6.888
65.977
38.806
9.63


2247
GLU
CB
6.755
65.653
35.442
9.81


2248
GLU
CG
5.280
65.882
35.870
17.01


2249
GLU
CD
4.989
67.337
36.130
20.22


2250
GLU
OE1
5.765
68.150
35.672
20.12


2251
GLU
OE2
4.011
67.716
36.770
21.83


2252
GLY
N
7.672
64.081
37.850
12.33


2253
GLY
CA
7.383
63.246
39.008
12.09


2254
GLY
C
8.175
63.692
40.243
13.63


2255
GLY
O
7.770
63.523
41.398
15.75


2256
ALA
N
9.326
64.327
39.971
12.57


2257
ALA
CA
10.116
64.799
41.081
14.07


2258
ALA
C
9.322
65.821
41.954
16.52


2259
ALA
O
9.483
65.941
43.167
16.67


2260
ALA
CB
11.371
65.387
40.495
12.23


2261
LYS
N
8.393
66.507
41.280
16.77


2262
LYS
CA
7.541
67.398
42.059
18.39


2263
LYS
C
6.832
66.678
43.258
17.76


2264
LYS
O
6.865
67.105
44.408
19.35


2265
LYS
CB
6.506
68.005
41.124
17.12


2266
LYS
CG
7.090
68.856
39.992
14.36


2267
LYS
CD
5.966
69.306
39.075
15.39


2268
LYS
CE
6.435
70.134
37.894
16.39


2269
LYS
NZ
5.285
70.300
36.996
21.56


2270
PHE
N
6.264
65.515
42.907
14.95


2271
PHE
CA
5.549
64.731
43.913
14.55


2272
PHE
C
6.529
64.115
44.923
15.10


2273
PHE
O
6.356
64.173
46.135
14.00


2274
PHE
CB
4.737
63.652
43.197
14.81


2275
PHE
CG
4.063
62.700
44.139
15.08


2276
PHE
CD1
4.788
61.680
44.744
16.62


2277
PHE
CD2
2.722
62.833
44.438
14.90


2278
PHE
CE1
4.201
60.834
45.687
14.26


2279
PHE
CE2
2.122
61.981
45.359
13.81


2280
PHE
CZ
2.854
60.983
45.992
11.28


2281
ILE
N
7.602
63.516
44.369
15.29


2282
ILE
CA
8.620
62.994
45.271
14.87


2283
ILE
C
9.098
64.058
46.323
18.20


2284
ILE
O
9.269
63.810
47.523
18.22


2285
ILE
CB
9.781
62.450
44.423
13.45


2286
ILE
CG1
9.314
61.364
43.436
10.62


2287
ILE
CG2
10.886
61.886
45.294
11.70


2288
ILE
CD1
8.566
60.206
44.086
4.61


2289
MET
N
9.239
65.281
45.809
18.52


2290
MET
CA
9.792
66.326
46.640
18.33


2291
MET
C
8.732
67.081
47.515
19.20


2292
MET
O
8.959
68.195
47.962
19.72


2293
MET
CB
10.605
67.243
45.721
17.77


2294
MET
CG
11.851
66.555
45.143
19.38


2295
MET
SD
12.907
65.705
46.383
20.87


2296
MET
CE
13.821
67.149
46.923
16.05


2297
GLY
N
7.574
66.434
47.745
18.14


2298
GLY
CA
6.695
66.952
48.792
18.26


2299
GLY
C
5.452
67.686
48.275
20.47


2300
GLY
O
4.563
68.022
49.049
22.07


2301
ASP
N
5.356
67.942
46.965
20.50


2302
ASP
CA
4.108
68.483
46.437
17.37


2303
ASP
C
3.162
67.337
46.013
17.32


2304
ASP
O
2.919
67.081
44.841
18.62


2305
ASP
CB
4.439
69.421
45.276
19.62


2306
ASP
CG
3.154
70.077
44.730
24.90


2307
ASP
OD1
2.113
69.959
45.386
26.11


2308
ASP
OD2
3.181
70.716
43.684
25.14


2309
SER
N
2.580
66.630
46.985
16.61


2310
SER
CA
1.600
65.618
46.540
16.15


2311
SER
C
0.437
66.083
45.684
16.64


2312
SER
O
−0.191
65.274
45.017
19.31


2313
SER
CB
1.018
64.974
47.843
16.12


2314
SER
OG
1.977
64.473
48.858
18.84


2315
SER
N
0.137
67.393
45.713
16.18


2316
SER
CA
−1.081
67.847
45.042
14.76


2317
SER
C
−1.003
67.619
43.503
14.88


2318
SER
O
−2.019
67.519
42.820
15.72


2319
SER
CB
−1.161
69.349
45.254
13.96


2320
SER
OG
−0.260
70.137
44.401
22.60


2321
VAL
N
0.253
67.507
43.003
13.31


2322
VAL
CA
0.437
67.281
41.570
14.74


2323
VAL
C
−0.202
65.960
41.092
15.66


2324
VAL
O
−0.608
65.824
39.951
13.81


2325
VAL
CB
1.896
67.243
41.083
15.18


2326
VAL
CG1
2.814
66.190
41.711
12.54


2327
VAL
CG2
2.515
68.549
40.598
15.63


2328
GLN
N
−0.243
64.979
42.006
16.96


2329
GLN
CA
−0.793
63.684
41.636
18.92


2330
GLN
C
−2.226
63.773
41.066
21.43


2331
GLN
O
−2.521
63.253
39.993
24.69


2332
GLN
CB
−0.734
62.761
42.839
17.47


2333
GLN
CG
−1.288
61.371
42.515
18.74


2334
GLN
CD
−0.938
60.331
43.569
18.38


2335
GLN
OE1
−0.084
60.526
44.399
19.34


2336
GLN
NE2
−1.630
59.234
43.514
18.40


2337
ASP
N
−3.081
64.507
41.797
23.31


2338
ASP
CA
−4.435
64.639
41.265
24.99


2339
ASP
C
−4.498
65.555
40.036
24.90


2340
ASP
O
−5.371
65.464
39.191
27.85


2341
ASP
CB
−5.359
65.090
42.386
30.46


2342
ASP
CG
−5.898
63.864
43.139
38.34


2343
ASP
OD1
−6.096
62.796
42.538
41.41


2344
ASP
OD2
−6.133
63.968
44.331
40.64


2345
GLN
N
−3.481
66.421
39.920
24.19


2346
GLN
CA
−3.341
67.176
38.686
24.10


2347
GLN
C
−3.036
66.310
37.465
22.53


2348
GLN
O
−3.619
66.479
36.402
22.16


2349
GLN
CB
−2.236
68.189
38.854
27.88


2350
GLN
CG
−2.519
69.162
39.994
35.96


2351
GLN
CD
−1.452
70.219
39.986
41.70


2352
GLN
OE1
−1.042
70.696
38.939
46.03


2353
GLN
NE2
−0.989
70.532
41.190
41.69


2354
TRP
N
−2.111
65.357
37.651
20.33


2355
TRP
CA
−1.847
64.398
36.574
17.39


2356
TRP
C
−3.136
63.679
36.183
17.81


2357
TRP
O
−3.426
63.468
35.016
19.79


2358
TRP
CB
−0.830
63.332
36.993
13.77


2359
TRP
CG
0.516
63.940
37.335
10.55


2360
TRP
CD1
1.046
65.159
36.878
9.50


2361
TRP
CD2
1.470
63.387
38.256
8.89


2362
TRP
NE1
2.254
65.372
37.454
9.63


2363
TRP
CE2
2.563
64.307
38.309
9.34


2364
TRP
CE3
1.485
62.233
38.992
7.20


2365
TRP
CZ2
3.624
64.047
39.152
6.71


2366
TRP
CZ3
2.570
61.964
39.836
8.42


2367
TRP
CH2
3.652
62.866
39.910
6.38


2368
LYS
N
−3.920
63.356
37.205
19.50


2369
LYS
CA
−5.171
62.681
36.902
22.56


2370
LYS
C
−6.181
63.495
36.071
23.90


2371
LYS
O
−6.735
63.007
35.084
23.96


2372
LYS
CB
−5.799
62.361
38.218
24.50


2373
LYS
CG
−7.008
61.458
38.044
28.26


2374
LYS
CD
−7.501
61.118
39.433
34.93


2375
LYS
CE
−8.576
60.059
39.389
39.02


2376
LYS
NZ
−9.083
59.968
40.759
41.94


2377
GLU
N
−6.383
64.761
36.493
23.93


2378
GLU
CA
−7.181
65.678
35.682
24.58


2379
GLU
C
−6.649
65.760
34.242
21.99


2380
GLU
O
−7.318
65.458
33.269
22.01


2381
GLU
CB
−7.206
67.072
36.321
30.24


2382
GLU
CG
−7.960
67.120
37.657
42.65


2383
GLU
CD
−9.484
67.012
37.473
50.82


2384
GLU
OE1
10.159
68.045
37.475
54.25


2385
GLU
OE2
−9.972
65.894
37.327
54.41


2386
LEU
N
−5.361
66.102
34.158
21.08


2387
LEU
CA
−4.739
66.203
32.844
22.45


2388
LEU
C
−4.934
65.008
31.923
23.20


2389
LEU
O
−5.055
65.104
30.712
23.99


2390
LEU
CB
−3.233
66.395
33.046
20.54


2391
LEU
CG
−2.790
67.845
33.160
18.96


2392
LEU
CD1
−1.487
68.124
33.900
20.13


2393
LEU
CD2
−3.847
68.949
33.168
19.21


2394
SER
N
−4.864
63.864
32.562
23.38


2395
SER
CA
−4.721
62.687
31.728
22.92


2396
SER
C
−6.100
62.254
31.142
23.30


2397
SER
O
−6.151
61.450
30.228
24.72


2398
SER
CB
−4.319
61.591
32.750
22.16


2399
SER
OG
−5.473
60.975
33.415
27.77


2400
HIS
N
−7.184
62.819
31.732
25.90


2401
HIS
CA
−8.537
62.618
31.210
28.59


2402
HIS
C
−9.030
61.156
31.255
30.18


2403
HIS
O
−9.507
60.620
30.270
30.25


2404
HIS
CB
−8.602
63.146
29.769
30.95


2405
HIS
CG
−8.313
64.620
29.712
34.62


2406
HIS
ND1
−7.438
65.162
28.838
36.95


2407
HIS
CD2
−8.885
65.653
30.480
34.71


2408
HIS
CE1
−7.474
66.484
29.058
38.33


2409
HIS
NE2
−8.339
66.806
30.042
36.25


2410
GLU
N
−8.866
60.555
32.442
32.02


2411
GLU
CA
−8.880
59.114
32.550
32.12


2412
GLU
C
10.319
58.458
32.274
34.76


2413
GLU
O
10.404
57.302
31.847
35.29


2414
GLU
CB
−8.241
58.464
33.758
32.31


2415
GLU
CG
−8.829
58.921
35.045
34.00


2416
GLU
CD
−8.282
58.062
36.156
35.79


2417
GLU
OE1
−7.104
57.728
36.149
34.22


2418
GLU
OE2
−9.052
57.673
37.019
40.13


2419
ASP
N
11.327
59.215
32.616
37.80


2420
ASP
CA
12.729
58.834
32.627
40.36


2421
ASP
C
13.412
58.996
31.213
42.09


2422
ASP
OCT1
13.102
59.944
30.481
43.37


2423
ASP
CB
13.289
59.623
33.836
41.96


2424
ASP
CG
12.785
58.974
35.133
47.10


2425
ASP
OD1
12.786
57.758
35.206
47.56


2426
ASP
OD2
12.374
59.654
36.072
50.59


2427
ASP
OCT2
14.223
58.147
30.834
44.87


2428
HOH
O
1.590
36.257
19.829
22.41


2429
HOH
O
8.296
45.178
41.518
8.41


2430
HOH
O
9.270
50.471
21.734
19.65


2431
HOH
O
7.577
61.174
51.241
16.06


2432
HOH
O
18.943
38.939
37.699
17.27


2433
HOH
O
22.811
45.617
27.594
16.66


2434
HOH
O
6.371
36.383
28.124
13.20


2435
HOH
O
9.209
32.873
26.183
14.51


2436
HOH
O
16.479
44.901
44.793
23.25


2437
HOH
O
8.760
29.925
27.422
20.25


2438
HOH
O
4.215
58.428
19.845
22.23


2439
HOH
O
9.419
63.753
24.541
24.52


2440
HOH
O
−0.851
27.498
26.895
29.29


2441
HOH
O
15.941
25.654
27.134
22.26


2442
HOH
O
19.413
32.977
27.432
12.77


2443
HOH
O
27.512
49.614
31.335
40.23


2444
HOH
O
−0.436
61.801
47.891
47.15


2445
HOH
O
21.459
47.078
25.096
17.33


2446
HOH
O
2.837
27.864
27.715
17.29


2447
HOH
O
5.024
60.810
49.088
29.47


2448
HOH
O
20.997
29.985
32.990
39.54


2449
HOH
O
10.885
59.567
51.200
19.14


2450
HOH
O
16.023
56.714
18.058
21.46


2451
HOH
O
8.071
59.483
19.187
23.78


2452
HOH
O
22.091
57.680
39.956
22.67


2453
HOH
O
19.064
49.798
21.891
21.33


2454
HOH
O
−5.143
44.798
23.400
15.49


2455
HOH
O
1.980
66.688
31.326
25.33


2456
HOH
O
17.162
41.413
37.458
26.52


2457
HOH
O
−1.859
60.380
39.401
20.12


2458
HOH
O
−4.668
51.480
41.919
15.16


2459
HOH
O
4.708
30.728
44.704
22.73


2460
HOH
O
9.740
65.513
50.805
38.71


2461
HOH
O
1.814
50.953
17.669
30.06


2462
HOH
O
15.786
35.633
20.587
12.33


2463
HOH
O
1.462
57.677
45.374
23.51


2464
HOH
O
9.068
56.054
44.758
18.52


2465
HOH
O
25.060
34.834
23.092
34.44


2466
HOH
O
1.037
20.342
34.088
47.03


2467
HOH
O
16.506
29.904
19.735
17.43


2468
HOH
O
20.557
38.125
16.713
33.14


2469
HOH
O
10.887
44.145
44.506
27.05


2470
HOH
O
12.790
34.400
33.238
10.97


2471
HOH
O
13.677
30.353
37.505
59.66


2472
HOH
O
−3.086
57.405
41.033
36.02


2473
HOH
O
12.385
42.893
25.595
46.73


2474
HOH
O
21.344
47.271
40.333
20.06


2475
HOH
O
25.419
45.911
39.851
27.74


2476
HOH
O
9.958
57.066
20.295
16.04


2477
HOH
O
13.824
63.678
20.576
37.51


2478
HOH
O
1.949
34.748
41.972
16.46


2479
HOH
O
11.924
25.680
18.786
24.92


2480
HOH
O
8.764
31.931
16.917
30.52


2481
HOH
O
−4.221
36.972
46.588
28.63


2482
HOH
O
13.821
31.194
39.085
34.61


2483
HOH
O
6.696
27.669
43.269
29.04


2484
HOH
O
0.694
24.349
39.414
33.75


2485
HOH
O
3.032
49.405
45.063
12.51


2486
HOH
O
9.849
48.468
46.210
29.19


2487
HOH
O
23.380
28.613
22.797
25.48


2488
HOH
O
10.046
47.774
27.577
19.52


2489
HOH
O
21.363
43.357
41.852
34.99


2490
HOH
O
19.727
38.364
41.922
52.15


2491
HOH
O
13.859
55.007
29.048
33.35


2492
HOH
O
14.515
57.104
53.219
21.80


2493
HOH
O
−9.836
29.524
39.997
26.93


2494
HOH
O
15.693
44.242
14.713
25.00


2495
HOH
O
−0.431
50.825
24.089
17.41


2496
HOH
O
4.304
42.234
42.012
13.63


2497
HOH
O
7.488
43.798
44.456
22.44


2498
HOH
O
−7.835
34.880
45.632
36.15


2499
HOH
O
2.138
68.198
50.281
19.61


2500
HOH
O
2.980
26.111
37.904
31.74


2501
HOH
O
7.532
71.080
47.284
47.61


2502
HOH
O
23.456
43.284
24.031
33.57


2503
HOH
O
12.879
33.827
17.029
41.26


2504
HOH
O
20.888
52.812
40.217
32.00


2505
HOH
O
−9.383
62.551
34.350
30.07


2506
HOH
O
−8.835
48.846
24.502
42.77


2507
HOH
O
9.650
31.084
37.437
29.51


2508
HOH
O
26.005
51.793
38.260
31.70


2509
HOH
O
24.046
63.460
39.268
43.53


2510
HOH
O
19.228
57.561
17.667
36.93


2511
HOH
O
29.104
43.058
29.224
34.73


2512
HOH
O
−3.271
63.254
48.607
39.25


2513
HOH
O
−8.324
51.286
27.830
31.97


2514
HOH
O
21.456
64.000
35.006
51.35


2515
HOH
O
−8.889
27.216
28.324
24.05


2516
HOH
O
−7.122
39.723
21.296
25.00


2517
HOH
O
8.123
69.041
34.700
34.79


2518
HOH
O
11.982
38.083
21.811
25.95


2519
HOH
O
4.694
64.020
48.437
21.02


2520
HOH
O
17.885
25.230
29.617
36.99


2521
HOH
O
19.286
25.222
33.390
42.05


2522
HOH
O
−8.562
44.803
26.142
51.85


2523
HOH
O
−2.242
26.527
23.393
43.07


2524
HOH
O
15.970
32.954
18.673
44.57


2525
HOH
O
16.957
72.759
19.740
41.48


2526
HOH
O
18.945
40.529
27.705
20.81


2527
HOH
O
−6.563
33.542
23.890
44.78


2528
HOH
O
0.655
54.144
15.969
48.10


2529
HOH
O
15.452
42.847
26.665
67.31


2530
HOH
O
−5.796
57.757
39.132
35.87


2531
HOH
O
19.494
43.627
13.835
34.84


2532
HOH
O
8.922
55.846
16.058
55.98


2533
HOH
O
12.263
58.246
17.626
37.03


2534
HOH
O
14.753
66.276
52.641
30.00


2535
HOH
O
−0.697
58.698
48.711
56.27


2536
HOH
O
4.631
63.608
25.321
39.92


2537
HOH
O
26.057
51.777
34.940
56.34


2538
HOH
O
25.752
58.882
40.841
54.74


2539
HOH
O
15.383
70.120
19.035
43.73


2540
HOH
O
−8.062
21.118
40.565
30.10


2541
HOH
O
−5.664
37.797
19.071
34.90


2542
HOH
O
21.557
47.692
21.844
42.58


2543
HOH
O
16.120
23.050
31.744
38.14


2544
HOH
O
14.291
55.688
33.958
43.49


2545
HOH
O
22.485
41.730
21.237
47.32


2546
HOH
O
−3.228
63.778
28.090
44.59


2547
HOH
O
26.949
48.396
41.531
41.13


2548
HOH
O
23.942
39.006
22.657
43.94


2549
HOH
O
9.207
24.849
23.061
41.15


2550
HOH
O
6.750
71.340
43.221
54.51


2551
HOH
O
30.844
41.630
25.787
45.95


2552
HOH
O
−3.732
34.406
21.323
35.90


2553
HOH
O
−4.730
60.259
28.099
41.23


2554
HOH
O
25.149
31.323
20.979
58.72


2555
HOH
O
14.035
68.161
21.262
57.00


2556
HOH
O
12.454
34.648
27.576
54.08


2557
HOH
O
24.417
50.046
45.237
40.59


2558
HOH
O
5.535
36.921
48.195
32.86


2559
HOH
O
23.831
29.039
31.600
46.72


2560
HOH
O
21.844
62.478
48.694
45.22


2561
HOH
O
24.579
48.404
30.338
31.47


2562
HOH
O
14.659
31.918
30.697
18.81


2563
HOH
O
−1.318
30.530
47.378
31.01


2564
LIG
O1
13.892
44.198
17.349
17.64


2565
LIG
C2
13.816
45.044
18.486
15.35


2566
LIG
C3
12.387
45.372
18.768
14.39


2567
LIG
C4
11.353
45.039
17.981
14.98


2568
LIG
C5
11.543
44.211
16.758
12.97


2569
LIG
C6
12.784
43.377
17.076
16.70


2570
LIG
S7
11.937
46.075
20.258
13.76


2571
LIG
C8
10.288
45.912
19.771
14.99


2572
LIG
C9
10.047
45.402
18.557
16.33


2573
LIG
C10
8.663
45.297
17.953
14.29


2574
LIG
O11
8.537
45.250
16.765
16.29


2575
LIG
O12
7.552
45.243
18.690
11.51


2576
LIG
N13
9.206
46.366
20.611
15.13


2577
LIG
C14
9.318
47.070
21.737
13.37


2578
LIG
C15
7.975
47.489
22.364
13.19


2579
LIG
O16
7.777
48.528
22.914
14.53


2580
LIG
O17
7.008
46.559
22.413
13.61


2581
LIG
O18
10.375
47.351
22.323
12.30


2582
LIG
C19
14.638
46.212
18.060
13.64


2583
LIG
O20
15.877
45.679
17.667
12.90


2584
LIG
C21
16.713
45.231
18.698
11.97


2585
LIG
C22
17.949
44.543
18.423
14.27


2586
LIG
C23
18.635
44.315
19.609
13.98


2587
LIG
S24
17.780
44.784
21.023
15.89


2588
LIG
N25
16.601
45.291
20.050
12.72


2589
LIG
C26
18.462
44.268
17.177
16.50


2590
LIG
C27
19.670
43.576
17.086
13.27


2591
LIG
C28
20.396
43.313
18.253
13.47


2592
LIG
C29
19.871
43.620
19.501
12.46


2593
LIG
O30
18.420
45.879
21.625
15.41


2594
LIG
O31
17.376
43.603
21.782
15.88

## Claims

1. A method of inhibiting at least one intracellular or membrane-associated PTPase that has aspartic acid (Asp) in position 48 using the numbering for PTP1B, the method comprising exposing said at least one PTPase in which inhibition is intended to an inhibitor compound which fits spatially into the active site and the vicinity thereof, said compound comprising the following features and moieties:
I. a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and a hydrogen bond with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.5–4.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å; and
II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles




 wherein said acid or said isostere group forms a salt bridge to the side chain amino group of lysine 120 wherein the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said lysine 120 ranges from 3.4–4.1 Å; and
III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å; and at least one of features IV through V:
IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å; and
V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å; and
one or more of the following features VI–XXXVII:
VI. an amino group which forms a salt bridge to the side chain carboxylic acid group of aspartic acid 48 such that the distance between the nitrogen atom of said amino group and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 3.4–4.1 Å; and
VII. two oxygen atoms which form hydrogen bonds via a water molecule to the side chain carboxylic acid group of aspartic acid 48 such that the distance between each of the two oxygen atoms and the centroid of said water molecule ranges from 2.5–3.6 Å and that the distance between said water molecule and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 2.5–3.6 Å and that the distance between said two oxygen atoms ranges from 2.5–3.0 Å; and
VIII. a hydrophobic group that interacts with the side chain methylene groups of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the methylene groups of said tyrosine 46 ranges from 4.4–5.1 Å;
IX. a hydrophilic group that forms a hydrogen bond or forms a salt bridge with aspartic acid 181 such that the distance between the centroid of said hydrophilic group and the centroid of the carboxylic acid of said aspartic acid 181 ranges from 4.4–5.1 Å;
X. a hydrophobic group that interacts with tyrosine 46 and the methylene side chain atoms of arginine 47 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.7–5.2 Å and the centroid of the methylene side chain atoms of said arginine 47 ranges from 4.5–5.5 Å;
XI. a hydrophilic group that forms a hydrogen bond with the one or more hydrogen atoms donated by the guanidinium group of arginine 47 such that the distance between the centroid of said hydrophilic group and the guanidinium group of said arginine 47 ranges from 2.7–3.5 Å;
XII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of arginine 47 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said arginine 47 ranges from 2.7–4.0 Å;
XIII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said aspartic acid 48 ranges from 2.7–4.0 Å;
XIV. a hydrophilic group that interacts with the backbone amide carbonyl group of asparagine 44 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said asparagine 44 ranges from 2.7–4.0 Å;
XV. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 45 ranges from 2.7–4.0 Å;
XVI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 45 ranges from 2.7–4.0 Å;
XVII. a hydrophobic group that interacts with the side chain methylene groups of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 45 ranges from 4.4–5.1 Å;
XVIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of arginine 45 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said arginine 45 ranges from 2.7–4.0 Å;
XIX. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of tyrosine 46 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said tyrosine 46 ranges from 2.7–4.0 Å;
XX. a hydrophilic group that forms a hydrogen bond with the side chain amino group of lysine 41 such that the distance between the centroid of said hydrophilic group and the amino group of said lysine 41 ranges from 2.7–4.0 Å;
XXI. a hydrophobic group that interacts with the side chain methylene groups of lysine 41 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said lysine 41 ranges from 4.4–5.1 Å;
XXII. a hydrophobic group that interacts with the side chain methylene groups of leucine 88 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said leucine 88 ranges from 4.4–5.1 Å;
XXIII. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of serine 118 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said serine 118 ranges from 2.7–4.0 Å;
XXIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of leucine 119 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said leucine 119 ranges from 2.7–4.0 Å;
XXV. a hydrophilic group that forms a hydrogen bond with the one of the hydrogen atoms donated by the side chain amide nitrogen of glutamine 262 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glutamine 262 ranges from 2.7–4.0 Å;
XXVI. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide group nitrogen of glycine 259 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glycine 259 ranges from 2.7–4.0 Å;
XXVII. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the side chain guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXVIII. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
XXIX. a hydrophobic group that interacts with the side chain methylene groups of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 254 ranges from 4.4–5.1 Å;
XXX. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
XXXII. a hydrophobic group that interacts with the side chain methylene groups of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
XXXIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the backbone amide carbonyl group of said aspartic acid 48 ranges from 2.7–3.5 Å;
XXXIV. a hydrophobic group that interacts with the side chain atoms of methionine 258 such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.5–6.2 Å;
XXXV. a hydrophobic group that interacts with glycine 259 such that the distance between the centroid of said hydrophobic group and the centroid of the alpha-carbon atom of said glycine 259 ranges from 4.5–6.2 Å;
XXXVI. a hydrophobic group that interacts with phenylalanine 52 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic group of said phenylalanine 52 ranges from 4.1–9.1 Å; or
XXXVII. a hydrophobic group that interacts with methionine 258, glycine 259 and phenylalanine 52 being part of a hydrophobic pocket such that the distance between the centroid of said hydrophobic group and (i) the centroid of the side chain of said methionine 258 ranges from 4.1–7.2 Å, (ii) the centroid of said glycine 259 ranges from 4.7–7.7 Å, and (iii) the centroid of the side chain of said phenylalanine 52 ranges from 4.1–9.1 Å,

wherein said compound is of the Formula 1




wherein
n is 0, 1 or 2, with the proviso that n is 1 or 2 when m is 0;
m is 0, 1 or 2, with the proviso that m is 1 or 2 when n is 0;
X is S, O, or NR8;
Y is NR7, O, S, SO, or SO2;
R1 is hydrogen, COOR3, or selected from the following 5-membered heterocycles:




R2 is hydrogen, C1–C6alkyl, hydroxy, or NR9R10;
R3 is hydrogen, C1–C6alkyl, arylC1–C6alkyl, C1–C6alkylcarbonyloxyC1–C6alkyl, or C1–C6alkylcarbonyloxyarylC1–C6alkyl;
R4, R5 and R6 are independently hydrogen, trihalomethyl, C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, carboxy, carboxyC1–C6alkyl, C1–C6alkyloxy-carbonyl, aryloxycarbonyl, arylC1–C6alkyloxycarbonyl, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxy, arylC1–C6alkyloxy, arylC1–C6alkyloxyC1–C6alkyl, thio, C1–C6alkylthio, C1–C6alkylthioC1–C6alkyl, arylthio, arylC1–C6alkylthio, arylC1–C6alkylthioC1–C6alkyl, NR9R10, C1–C6alkylaminoC1–C6alkyl, arylC1–C6alkylaminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarbonylC1–C6alkyl, arylC1–C6alkylcarbonyl, arylC1–C6alkylcarbonylC1–C6alkyl, C1–C6alkylcarboxy, C1–C6alkylcarboxyC1–C6-alkyl, arylcarboxy, arylcarboxyC1–C6alkyl, arylC1–C6alkylcarboxy, arylC1–C6alkylcarboxyC1–C6alkyl, C1–C6alkylcarbonylamino, C1–C6alkylcarbonyl-aminoC1–C6alkyl, -carbonylNR7C1–C6alkylCOR13, arylC1–C6alkylcarbonyl-amino, arylC1–C6alkylcarbonylaminoC1–C6alkyl, CONR9R10, or C1–C6alkyl-CONR9R10 wherein the alkyl and aryl groups are optionally substituted and R13 is NR9R10, or C1–C6alkylNR9R10; R7 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkyloxocarbonyl, arylcarbonyl, aryloxocarbonyl, arylC1–C6alkylcarbonyl, arylC1–C6alkyloxocarbonyl, C1–C6alkylcarboxy, arylC1–C6alkylcarboxy, R9R10NcarbonylC1–C6alkyl wherein R9 and R0 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy; wherein the alkyl and aryl groups are optionally substituted;
R8 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkyl-carboxy wherein the alkyl and aryl groups are optionally substituted;
R9 and R10 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy wherein the alkyl and aryl groups are optionally substituted; or
R9 and R10 are together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system can optionally be substituted with at least one C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, C1–C6alkyloxy, arylC1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, NR11R12 or C1–C6alkylamino-C1–C6alkyl, wherein R11 and R12 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy; wherein the alkyl and aryl groups are optionally substituted; or
R9 and R10 are independently a saturated or partial saturated cyclic 5, 6 or 7 membered amine, imide or lactam;
or a salt thereof with a pharmaceutically acceptable acid or a base, or any optical isomer or mixture of isomers thereof, or any tautomer thereof.

2. The method of claim 1 wherein the compound is selected from the following:
5-(4-Chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(2,4-Dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4,5,6,7-Tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(1,3-Dioxo-1,3-dihydro-benzo[f]isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
Oxalic acid (3-carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl) ester methyl ester;
Oxalic acid (3-carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl) ester;
7-Hydroxymethyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(((Benzo[1,3]dioxole-5-carbonyl)-amino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(3-Imidazol-1-yl-2,5-dioxo-pyrrolidin-1-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
2-(Oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 7-ethyl ester;
7-Benzylcarbamoyl-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-(4-Chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(3-(2,4-Dimethoxy-phenyl)-ureidomethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
2-((3-Carboxy-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl)-carbamoyl)-nicotinic acid;
5-(4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(5,7-Dioxo-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindol-6-ylmethyl2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(2,4-Dioxo-5-pyridin-2-ylmethylene-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(2,4-Dioxo-5-pyridin-2-ylmethyl-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(5-(4-Methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(5-(4-Acetylamino-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(5-(3,5-Dimethoxy-benzylidene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(5-(1H-Imidazol-4(5)-ylmethylene)-2,4-dioxo-thiazolidin-3-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-((2-(4-Methanesulfonyl-phenyl)-acetylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(1,3-Dioxo-4,7-epoxido-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-((2-Amino-3-phenyl-propionylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(((2R)-2-Amino-3-phenyl-propionylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-((2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-((2-Acetylamino-3-methyl-butyrylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-c]pyridin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5-Nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(5-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-Nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
2-(Oxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
2-(Oxalyl-amino)-7-(3-oxo-3H-benzo[d]isoxazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-ethyl ester;
5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
(L)-5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 wherein the compound is selected from the following:
5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(((Benzo[1,3]dioxole-5-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(4-(4-Chloro-phenylsulfanyl)-6-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-(3-(2,4-Dimethoxy-phenyl)-ureidomethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-((2-(4-Methanesulfonyl-phenyl)acetylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
7-((2-Acetylamino-3-(4-hydroxy-phenyl)propionylamino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid;
5-(S)-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(4-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-5-(S)-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(7-Benzyloxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(7-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((5-Benzyloxy-1H-indole-2-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((6-Bromo-2-p-tolyl-quinoline-4-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
6-(4-Methoxy-benzyl)-7-(((5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((1H-Indole-3-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((4-Ethoxy-2-hydroxy-benzoylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((4-Benzoylamino-benzoylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((Biphenyl-4-carbonyl)-amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((1H-Indole-2-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((3-Biphenyl-4-yl-acryloylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c)pyridine-3-carboxylic acid;
6-(4-Methoxy-benzyl)-7-(((5-methoxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((4-Benzyl-benzoylamino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
6-(4-Methoxy-benzyl)-7-(((naphthalene-1-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
6-(4-Methoxy-benzyl)-5-((2-naphthalen-2-yl-ethylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-((2-Benzo[1,3]dioxol-5-yl-acetylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-((2-Dibenzofuran-2-yl-ethyl)amino)methyl)-6-(4-methoxy-benzyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
6-(4-Methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-H-indol-3-yl)-acetylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(R)-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(S)-(7-Methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(S)-(Oxalyl-amino)-5-((4-phenoxy-benzylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(S)-((4-Acetylamino-benzylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-((Acetyl-(4-phenoxy-benzyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-((Acetyl-benzyl-amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(S)-((1,1-Dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(4-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(6-Methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-7-(1,1,3-trioxo-1,3-dihydro-1H-benzo[d]isothiazol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(R)-Carbamoyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-5-(S)-phenylcarbamoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-7-(R)-phenylcarbamoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
5-(R),7-(R)-Bis-benzyloxymethyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
6-Benzyl-2-(oxalyl-amino)-5-(1,1,3-trioxo-1,3-dihydro-1,6-benzo[d]isothiazol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein said exposing step is effected by administering said compound to a mammal in need of said inhibition.

5. The method of claim 4 wherein said mammal has a disease selected from the group consisting of autoimmune diseases, acute and chronic inflammation, osteoporosis, cancers, type I diabetes, type II diabetes, and obesity.

6. The method of claim 4 wherein said mammal is a human.