lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
InChIKey: SDHFXINHZHARIB-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Extracellular Cytochrome P450 Inhibition Assay: Specific aspects of the incubation conditions for each assay (e.g., protein concentration, incubation time, etc.) are defined in Walsky & Obach, 2004 (Walsky, R. L., and Obach, R. S. Validated assays for human Cytochrome P450 activities. Drug Met. Disp. 32:647-660, 2004.). In general, microsomes at protein concentrations as defined in Table 12 were mixed with buffer (100 mM KH2PO4, pH 7.4), MgCl2 (6 mM)) and substrate, and were kept on ice. Aliquots of this mixture (89 μL) were delivered to each well of a 96-well polypropylene plate which contained an aliquot of inhibitor (1 μL) in acetonitrile:water (1:1). Final solvent concentrations were less than 1% (v/v). Incubations were initiated with the addition of 10 μL β-NADPH (10 mM stock) to a final volume of 100 μL. Incubations were terminated by the addition of 1.5-2× volume of acetonitrile containing internal standard (buspirone). Samples were centrifuged at 4° C., and supernatant was transferred for LC-MS/MS analysis.
Measurement: IC50 = 26000 nM (pChEMBL 4.579999923706055)
Descriptors: MW 459.61, ALogP 6.13, HBA 5, HBD 2, PSA 84.86, QED 0.49
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Protein mono-ADP-ribosyltransferase PARP10 (SINGLE PROTEIN), Homo sapiens
UniProt: Q53GL7
Assay: Inhibition of human recombinant N-terminal FLAG-tagged / C-terminal Strep-tagged PARP10 (805 to 1025 end residues) expressed in baculovirus infected Sf9 cells expression system incubated for 1 hr by ELISA assay
Measurement: IC50 > 5000 nM (pChEMBL 5.301000118255615)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4
Compound (SMILES): COCc1nn(Cc2ccc(Cn3cc(F)ccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: ZRUFVDPYHLTYPD-UHFFFAOYSA-N
Target: Coagulation factor XII (SINGLE PROTEIN), Homo sapiens
UniProt: P00748
Assay: Determination of the % Inhibition for FXIIa: Factor XIIa inhibitory activity in vitro was determined using standard published methods (see e.g. Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Baeriswyl et al., ACS Chem. Biol., 2015, 10 (8) 1861; Bouckaert et al., European Journal of Medicinal Chemistry 110 (2016) 181). Human Factor XIIa (Enzyme Research Laboratories) was incubated at 25° C. with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410 nm and the IC50 value for the test compound was determined.
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 509.51, ALogP 2.9, HBA 8, HBD 1, PSA 100.27, QED 0.35
Compound (SMILES): CC(C)c1c2cc(-c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3F)ccc2nn1C
InChIKey: LLFOBMRPWNABCB-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 4/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24385
Assay: Inhibition of CDK4/Cyclin D1 (unknown origin) transfected in HEK293 cells by NanoBRET assay
Measurement: IC50 = 5.2 nM (pChEMBL 8.279999732971191)
Descriptors: MW 446.53, ALogP 3.84, HBA 8, HBD 2, PSA 83.79, QED 0.48
Compound (SMILES): C[C@H](CC[C@](C)(O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
InChIKey: BVBRUQYHUXKZMQ-JNVAYQLDSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 (unknown origin)
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 456.63, ALogP 7.05, HBA 2, HBD 2, PSA 40.46, QED 0.45
Compound (SMILES): CC(C)N1CCOc2c(F)cc(-c3nc(Nc4ccc(C5CCN(C)CC5)cn4)ncc3F)cc21
InChIKey: YZSCPLGKKMSBMV-UHFFFAOYSA-N
Target: Macrophage colony-stimulating factor 1 receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P07333
Assay: LanthaScreen Eu Kinase Binding Assay: FMS: IC50 values of compounds against FMS kinase were determined by LanthaScreen™ Eu Kinase Binding Assay at Invitrogen (Life Technologies Grand Island, N.Y.) where total reaction volume was 10 μL in low-volume 384-well plates (#4511, Corning). Serially diluted compounds (3-fold) were incubated with kinase (1.25 nM) for 10 min, following which a mixture of ATP (10 μM) (#A1852, Sigma, St-Louis, Mo.) and fluorescent-PolyGT substrate (200 nM) (#PV3610, Invitrogen, Life Technologies Grand Island, N.Y.) was added and incubated in dark at room temperature for 1 h. After 1 h, 10 μL stop solution containing Terbium labeled antibody (4 nM) (#PV3529, Invitrogen, Life Technologies Grand Island, N.Y.) and EDTA (#E5134, Sigma, St-Louis, Mo.) (20 mM) in TR-FRET dilution buffer (#PV3574, Invitrogen, Life Technologies Grand Island, N.Y.) was added. Readings were taken in a Synergy Neo Plate reader (BioTek, Winooski) at single excitation of 340 nm and Dual emission at 495 nm and 520 nm respectively.
Measurement: IC50 = 353 nM (pChEMBL 6.449999809265137)
Descriptors: MW 480.56, ALogP 4.98, HBA 7, HBD 1, PSA 66.41, QED 0.55
Compound (SMILES): CC(C)CCN[C@@H]1CCc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2C1
InChIKey: DVFCRTGTEXUFIN-GFCCVEGCSA-N
Target: Tyrosine-protein phosphatase non-receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P17706
Assay: Inhibition of human PTPN2 extracted from Escherichia coli BL21 (DE3) by fluorescence based analysis
Measurement: IC50 = 1.8 nM (pChEMBL 8.739999771118164)
Descriptors: MW 385.46, ALogP 1.21, HBA 5, HBD 3, PSA 98.74, QED 0.71
Compound (SMILES): CO[C@@H]1CCN(c2nccc(Nc3cc4c(C(C)C)ccc(N5C[C@H](CS(C)(=O)=O)[C@H]5C)c4cn3)n2)C[C@@H]1F
InChIKey: LIMFPAAAIVQRRD-BCGVJQADSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of N-terminal GST tagged recombinant human EGFR ex19del (746 to 750) mutant expressed in baculovirus infected Sf9 insect cells expression system using 5-FAM-EEPLYINSFPAKKK-CONH peptide as substrate preincubated for 10 mins followed by peptide substrate addition in presence of ATP
Measurement: IC50 = 25 nM (pChEMBL 7.599999904632568)
Descriptors: MW 556.71, ALogP 4.32, HBA 9, HBD 1, PSA 100.55, QED 0.43
Compound (SMILES): O=C1COc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
InChIKey: PMKMNTBZJOXTJW-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1A (SINGLE PROTEIN), Homo sapiens
UniProt: P08908
Assay: Binding Assay: Receptor Source: Human recombinant expressed in HEK-293 cells  Radioligand: [3H]-8-OH-DPAT (221 Ci/mmol)  Control Compound: 8-OH-DPAT  Incubation Conditions: The reactions were carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgSO4, 0.5 mM EDTA and 0.1% Ascorbic acid at room temperature for 1 hour. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters was determined and compared to control values in order to ascertain any interactions of test compounds with the cloned serotonin—5HT1A binding site (Literature Reference: Hoyer, D. et al. Eur. Journal Pharmacol. 1985, 118, 13-23; Schoeffter, P. and Hoyer, D. Naunyn-Schmiedeberg's Arch. Pharmac. 1989, 340, 135-138)
Measurement: IC50 = 2.25 nM (pChEMBL 8.649999618530273)
Descriptors: MW 450.37, ALogP 4.31, HBA 5, HBD 1, PSA 54.04, QED 0.64
Compound (SMILES): COC[C@H](NC(=O)c1ccn(S(C)(=O)=O)c1)C(=O)Nc1nc(-c2cccc(N3C[C@@H](C)O[C@@H](C)C3)n2)cs1
InChIKey: JBLQNFBXKOAIHG-FCEWJHQRSA-N
Target: Cytochrome P450 2B6 (SINGLE PROTEIN), Homo sapiens
UniProt: P20813
Assay: Inhibition of CYP2B6 (unknown origin)
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 562.67, ALogP 1.81, HBA 11, HBD 2, PSA 144.75, QED 0.4
Compound (SMILES): Oc1ccc2c3c(cnc2c1)-c1ccc(C(F)(F)F)cc1O[C@@H]3c1ccc(OCCN2CC(CF)C2)cc1
InChIKey: UVBQMXOKKDCBJN-MUUNZHRXSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Induction of wild type ERalpha degradation in human MCF cells by high content imaging assay
Measurement: IC50 = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 524.51, ALogP 6.39, HBA 5, HBD 1, PSA 54.82, QED 0.3
Compound (SMILES): Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: TVGAHWWPABTBCX-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of human CYP3A4
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 431.5, ALogP 3.56, HBA 9, HBD 1, PSA 99.75, QED 0.5
Compound (SMILES): C[C@@H](N)c1cc(Cl)ccc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
InChIKey: BHKKSKOHRFHHIN-MRVPVSSYSA-N
Target: Myeloperoxidase (SINGLE PROTEIN), Homo sapiens
UniProt: P05164
Assay: Displacement of benzhydroxamic acid from native state MPO (unknown origin) by 1D NMR reporter assay
Measurement: Kd = 501.19 nM (pChEMBL 6.300000190734863)
Descriptors: MW 334.83, ALogP 3.11, HBA 4, HBD 3, PSA 79.6, QED 0.64
Compound (SMILES): CCc1cc2ncc(CN3CCN(c4ccc(C(=O)NC)nc4)CC3)cc2[nH]c1=O
InChIKey: WQAVGRAETZEADU-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UGN5
Assay: Inhibition of PARP-2 (unknown origin)
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 406.49, ALogP 1.56, HBA 6, HBD 2, PSA 94.22, QED 0.67
Compound (SMILES): CNC(=O)c1ccc(N2CCN(Cc3ccc4nc(C)c(=O)[nH]c4c3F)CC2)c(F)n1
InChIKey: WXRCLFFPZXJCLS-UHFFFAOYSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of hERG transfected in CHO cells by electrophysiology
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 428.44, ALogP 1.59, HBA 6, HBD 2, PSA 94.22, QED 0.61
Compound (SMILES): Cc1cnc(-c2cc(O[C@@H]3CCOC3)cc(C(=O)N[C@H](C)c3cnc(C(F)(F)F)nc3)c2)s1
InChIKey: GTQPEQGDLVSFJO-CXAGYDPISA-N
Target: Cytochrome P450 2C8 (SINGLE PROTEIN), Homo sapiens
UniProt: P10632
Assay: CYP Inhibition Assay: Human liver microsomes (pooled, >30 male and female donors) were incubated with individual CYP isoform-selective standard probes (phenacetin for CYP1A2, amodiquine for CYP2C8, diclofenac for CYP2C9, dextromethorphan for CYP2D6 and midazolam for CYP3A4) in the absence and presence of increasing concentrations of the test compound in order to compare the extent of formation of the respective metabolite. In addition, a set of incubation in the absence of test compound was used as a negative control. Furthermore, the inhibitory potency of standard inhibitors was included as positive controls (fluvoxamine for CYP1A2, montelukast for CYP2C8, sulfaphenazole for CYP2C9, fluoxetine for CYP2D6, ketoconazole for CYP3A4 and mibefradil for CYP3A4-preincubation). Incubation conditions (protein and probe substrate concentration, incubation time) were optimised with regard to linearity and metabolite turnover. Incubation medium consisted of 50 mM potassium phosphate buffer (pH 7.4) containing 1 mM EDTA, NADPH regenerating system (1 mM NADP, 5 mM glucose 6-phosphate, glucose 6-phosphate dehydrogenase (1.5 U/mL). Sequential dilutions and incubations were performed on a Genesis Workstation (Tecan, Crailsheim, FRG) in 96-well plates at 37° C. A final incubation volume of 200 μL was used. Reactions were stopped by addition of 100 μL acetonitrile containing the respective internal standard. Precipitated proteins were removed by centrifugation of the well plate, supernatants were combined and analyses were performed by LC-MS/MS. The LC-MS/MS quantification of the metabolites paracetamol (CYP1A2), desethylamodiaquine (CYP2C8), 4-hydroxydiclofenac (CYP2C9), dextrorphan (CYP2D6), and 1-hydroxymidazolam (CYP3A4) was performed with a PE SCIEX API 3000 LC/MS/MS system (Applied Biosystems, MDS Sciex, Concord, Ontario, Canada).
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 478.5, ALogP 4.59, HBA 7, HBD 1, PSA 86.23, QED 0.56
Compound (SMILES): NCCCC[C@H](NC(=O)C1CCCC1)C(=O)COc1c(F)ccc(F)c1F
InChIKey: OLIMBXKACVCIMM-HNNXBMFYSA-N
Target: Pro-cathepsin H (SINGLE PROTEIN), Homo sapiens
UniProt: P09668
Assay: Inhibition of Lysine Gingipain: The capacities of compounds of the present invention to inhibit the activity of lysine gingipain were measured in a fluorogenic assay similar to those described by Barret (Biochemical Journal. 1980, 187(3), 909). The specific assay conditions were as follows. Buffer: pH=7.5, 100 mM Tris-HCl, 75 mM NaCl, 2.5 mM CaCl2), 10 mM cysteine, 1% DMSO after all additions. Protein: 0.1 nM Kgp, isolated from culture of Porphyromonas gingivalis, as described by Pike et al. (J. Biol. Chem. 1994, 269(1), 406), and Potempa and Nguyen (Current Protocols in Protein Science. 2007, 21.20.1-21.20.27). Fluorogenic substrate: 10 μM Z-His-Glu-Lys-MCA. Time=90 minutes. Temperature=37° C. Each compound: 10 concentrations, starting at either 100 μM or 100 nM, with lower concentrations generated by serial 3-fold dilutions. By testing a range of concentrations for each compound, the concentration required to inhibit the activity of lysine gingipain by 50% (the IC50) was determined. Under the described assay conditions, the signal-to-noise ratio was excellent, and the Z factor was greater than 0.6. Compounds in Table 1 were tested, as well as the compounds set forth in Table 2 below.The capacities of compounds of the present invention to inhibit the activity of cathepsins B, H, K, L, and S were measured in similar assays. Boc-Leu-Arg-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin B assay. L-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin H assay. Z-Phe-Arg-AMC (10 μM) in HEPES buffer (50 mM, pH 7.4) containing DTT (2.5 mM) and EDTA (1 mM) was used for the Cathepsin K assay. Z-Phe-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin L assay. Z-Leu-Arg-AMC (10 μM) in sodium acetate buffer (25 mM, pH 4.5) containing DTT (2.5 mM) and NaCl (50 mM) was used for the Cathepsin S assay.
Measurement: IC50 = 560 nM (pChEMBL 6.25)
Descriptors: MW 386.41, ALogP 2.86, HBA 4, HBD 2, PSA 81.42, QED 0.48
Compound (SMILES): CC(=O)N1CCN([C@H]2CCC[C@@H](NC(=O)c3cc4c(F)ccc(C)c4[nH]3)C2)CC1
InChIKey: PGNLXEBQMQHFNK-SJORKVTESA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 in human liver microsomes using tolbutamide as substrate preincubated for 5 mins followed by NADPH addition measured after 20 mins by LC-MS/MS analysis
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 400.5, ALogP 2.82, HBA 3, HBD 2, PSA 68.44, QED 0.83
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 in human liver microsomes assessed as reduction in 4 hydroxy-diclofenac metabolite formation incubated for 30 mins in presence of NADPH by LC-MS/MS analysis
Measurement: IC50 > 25000 nM (pChEMBL 4.6020002365112305)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): Cc1c(Nc2c(F)ccc(NS(=O)(=O)CCCF)c2Cl)ccc2ncn(C)c(=O)c12
InChIKey: VVLVISDSGRHLMB-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: BRAF V600E and V600K Enzyme Assay: A competitive displacement assay was configured for B-Raf that monitors the amount of a fluorescently-tagged tracer bound to B-Raf via TR-FRET from an anti-tag Eu-labeled antibody also bound to B-Raf. For full-length FLAG-tagged B-Raf(V600E), the assay mixtures consisted of 25 mM K+HEPES, pH 7.4, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT, 2% DMSO (from compound), 50 nM Tracer 1710 (ThermoFisher, PR9176A), 0.5 nM Eu anti-FLAG (M2)-cryptate Ab (Cisbio, 61FG2KLB) and 5 nM full-length, N-terminally FLAG-tagged B-Raf(V600E) (Origene Technologies, TP700031. When B-Raf(V600K) was assayed, the following substitutions were made: 15 nM Tracer 178 (ThermoFisher, PV5593), 2 nM Eu-anti-GST Ab (ThermoFisher, PV5595) and 5 nM N-terminally GST-tagged B-Raf(V600K) (331-end, SignalChem, B08-12DG). Compounds were typically diluted in DMSO across an 11-point dosing range created using a 3-fold serial dilution protocol at a top dose of 10 μM. The assay was run in 384-well, polystyrene, low-volume, non-treated, white microtiter plates (Costar 4512) in a final volume of 12 μL. Low control wells included 1 μM of a potent B-Raf inhibitor as a control.
Measurement: IC50 = 3.25 nM (pChEMBL 8.489999771118164)
Descriptors: MW 456.9, ALogP 3.88, HBA 6, HBD 2, PSA 93.09, QED 0.56
Compound (SMILES): CC1(C)Cn2nc(-c3ccc(F)cn3)c(-c3ccnc4[nH]ncc34)c2CO1
InChIKey: WZMIWVZGYMKUDV-UHFFFAOYSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 in human liver microsomes incubated for 10 mins in presence of NADPH by LC-MS/MS analysis
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 364.38, ALogP 3.33, HBA 6, HBD 1, PSA 81.51, QED 0.59
Compound (SMILES): COc1ccc2nc3ccc(OC)cc3c(SCCCN)c2c1
InChIKey: ZFOMCSNUEHMROO-UHFFFAOYSA-N
Target: Dual specificity protein kinase CLK2 (SINGLE PROTEIN), Homo sapiens
UniProt: P49760
Assay: Inhibition of recombinant human CLK2 expressed in Sf9 insect cells incubated for 60 mins in presence of ATP and [gamma33-P] ATP by radiometric scintillation counter analysis
Measurement: IC50 = 2674 nM (pChEMBL 5.570000171661377)
Descriptors: MW 328.44, ALogP 3.85, HBA 5, HBD 1, PSA 57.37, QED 0.42
Compound (SMILES): CC(C)C(=O)Nc1ncc(C(=O)NCCN(Cc2ccccc2)C(=O)c2ccc(S(=O)(=O)Nc3ccccc3)cc2)s1
InChIKey: YVPYJSSYGACUSE-UHFFFAOYSA-N
Target: LIM domain kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P53671
Assay: Inhibition of LIMK2 in human HeLa cells lysate incubated for 45 mins by kinobead based pulldown assay
Measurement: IC50 = 368 nM (pChEMBL 6.429999828338623)
Descriptors: MW 605.74, ALogP 4.61, HBA 7, HBD 3, PSA 137.57, QED 0.22
Compound (SMILES): CN(CCCNC(=O)c1cc2ccccc2o1)Cc1ccccc1
InChIKey: JOJSGPZOAORNJM-UHFFFAOYSA-N
Target: Atypical chemokine receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P25106
Assay: Agonist activity at human ACKR3 transfected in HEK293T cells co-expressing LgBiT-fused SmBiT-beta-arrestin assessed as beta-arrestin recruitment by bioluminescence based NanoBiT assay
Measurement: EC50 = 1480 nM (pChEMBL 5.829999923706055)
Descriptors: MW 322.41, ALogP 3.68, HBA 3, HBD 1, PSA 45.48, QED 0.67
Compound (SMILES): CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC(=O)N3)[C@H]2C[C@H]21)c1ccc(Cl)cc1
InChIKey: RXNPEQZHMGFNAY-GEALJGNFSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 in human liver microsomes at 0.01 to 30 uM using mephenytoin as substrate in presence of NADPH by UPLC-MS/MS analysis
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 483.02, ALogP 3.15, HBA 6, HBD 2, PSA 90.46, QED 0.66
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@@H](NC(=O)CN)CSSC[C@@H]2NC(=O)[C@@H]3CSSC[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N4C[C@@H](O)C[C@H]4C(=O)N4C[C@@H](O)C[C@H]4C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)O)NC(=O)[C@H](Cc4cnc[nH]4)NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc4c[nH]c5ccccc45)NC(=O)CNC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC1=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H]([C@@H](C)O)NC2=O
InChIKey: ZVNYDGYMISSIMY-MCQYGHRBSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Modulator activity at human Nav1.7 expressed in Xenopus laevis oocytes assessed as elicitation in sodium current measured after 1 to 4 days by two-electrode voltage clamp assay
Measurement: EC50 = 73 nM (pChEMBL 7.139999866485596)
Descriptors: MW 3318.76
Compound (SMILES): Cc1ccc(C(=O)Nc2ccc3c(c2)C(F)(F)C[C@@H]3N2CCN(C)CC2)cc1C#Cc1cnc2cccnn12
InChIKey: BPLVEFPXYUJTQJ-MHZLTWQESA-N
Target: Fibroblast growth factor receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11362
Assay: Inhibition of human FGFR1 using KKKSPGEYVNIEFG as substrate incubated for 30 mins followed by 33P-ATP addition and measured after 2 hrs by liquid scintillation counter method
Measurement: IC50 < 10 nM (pChEMBL 8)
Descriptors: MW 526.59, ALogP 4.47, HBA 6, HBD 1, PSA 65.77, QED 0.4
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H]2CSSC[C@H](NC1=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1ccccc1)C(=O)N(C)[C@@H](CCCNC(=N)N)C(=O)N(C)[C@@H](Cc1c[nH]c3ccccc13)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N2
InChIKey: YMCLJESYNLOGEG-SOJQCDDKSA-N
Target: Melanocortin receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P33032
Assay: Displacement of [125I]-NDP-alpha-MSH from human MC5R expressed in HEK2936E cell membrane measured after 16-23 hrs by 1450 microbeta trilux scintillation proximity assay
Measurement: IC50 = 724.44 nM (pChEMBL 6.139999866485596)
Descriptors: MW 1695.06
Compound (SMILES): C=CC(=O)Nc1cc(N2CCN(C)CC2)ccc1Nc1ncc2c(n1)-n1ccc(C(=O)Nc3c(CC)cccc3CC)c1CC2
InChIKey: QMTKZAHTDPRIFJ-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P22455
Assay: Inhibition of human recombinant FGFR4 expressed in Sf9 insect cells using poly[Glu:Tyr] 4:1 as substrate in presence of [33P]-ATP by radiometric hotspot kinetic assay
Measurement: IC50 = 2750 nM (pChEMBL 5.559999942779541)
Descriptors: MW 604.76, ALogP 5.36, HBA 8, HBD 3, PSA 107.42, QED 0.22
Compound (SMILES): CCc1cc(O)c(F)cc1-c1cc(N[C@@H](C)CO)c2nc(NCCOCCN(C)C)ncc2c1
InChIKey: XXYVYULKAZLNBS-INIZCTEOSA-N
Target: JAK3/JAK1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P52333
Assay: Inhibition of JAK1/JAK3 signalling in human PBMC assessed as inhibition of IL-2 stimulated IFN-gamma release incubated for 1 hr followed by IL-2 stimulation by MSD assay
Measurement: IC50 = 251.19 nM (pChEMBL 6.599999904632568)
Descriptors: MW 471.58, ALogP 3.49, HBA 8, HBD 4, PSA 102.77, QED 0.3
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CCCNC(=N)N)N(C)C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]2CSSC[C@H](NC1=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1ccccc1)C(=O)N(C)[C@@H](CCCNC(=N)N)C(=O)N(C)[C@@H](Cc1c[nH]c3ccccc13)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N2
InChIKey: VDHCRROJIVFVLM-BCHBBXIYSA-N
Target: Melanocortin receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P33032
Assay: Displacement of [125I]-NDP-alpha-MSH from human MC5R expressed in HEK2936E cell membrane measured after 16-23 hrs by 1450 microbeta trilux scintillation proximity assay
Measurement: IC50 = 380.19 nM (pChEMBL 6.420000076293945)
Descriptors: MW 1995.38
Compound (SMILES): O=C(NCCCn1ccnc1)c1cc2nc(-c3ccccc3)cc(-c3ccccc3)n2n1
InChIKey: RIGHCDSORZCRDE-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1D (SINGLE PROTEIN), Homo sapiens
UniProt: P28221
Assay: GPCRScan assay: inhibition of 5-HT1D
Measurement: Ki = 316.23 nM (pChEMBL 6.5)
Descriptors: MW 422.49, ALogP 4.08, HBA 6, HBD 1, PSA 77.11, QED 0.4
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CCCNC(=N)N)N(C)C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H]2CSSC[C@H](NC1=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1c[nH]c3ccccc13)C(=O)N[C@@H](C)C(=O)N2
InChIKey: LICCWOCOLMEXQP-HKMYQXKPSA-N
Target: Melanocortin receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P33032
Assay: Displacement of [125I]-NDP-alpha-MSH from human MC5R expressed in HEK2936E cell membrane measured after 16-23 hrs by 1450 microbeta trilux scintillation proximity assay
Measurement: IC50 = 630.96 nM (pChEMBL 6.199999809265137)
Descriptors: MW 1826.19
Compound (SMILES): CCNCCc1ccc(Cl)c(-c2ccccc2OC)c1.Cl
InChIKey: SXOXLJQRLIFVCQ-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1D (SINGLE PROTEIN), Homo sapiens
UniProt: P28221
Assay: Binding affinity to 5-HT1DR (unknown origin)
Measurement: Ki = 5.3 nM (pChEMBL 8.279999732971191)
Descriptors: MW 289.81, ALogP 4.17, HBA 2, HBD 1, PSA 21.26, QED 0.81
Compound (SMILES): CN1CCN(c2cc(F)c(-c3ccc(C(=O)N(C)C)cc3)cc2Nc2ncnc(Cl)c2N)CC1
InChIKey: LXONEMNSYOAQJT-UHFFFAOYSA-N
Target: N-lysine methyltransferase KMT5A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NQR1
Assay: Inhibition of SET8 (unknown origin) assessed as effect on H4K20 methylation incubated for 30 mins by Alphascreen assay
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 483.98, ALogP 3.72, HBA 7, HBD 2, PSA 90.62, QED 0.53
Compound (SMILES): Cc1nc(Nc2cccc(N3CCCC3=O)n2)sc1-c1cc2c(c(S(=O)(=O)NC3COC3)c1)C(=O)N([C@@H](C)C1CC1)C2
InChIKey: BHFJVMZATJXYCO-KRWDZBQOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Enzymatic Activity Assay : The activity of recombinant human PI3Kγ ((aa144-1102)-6His) and PI3Kα, β, δ (6-His(p110-p85α)) was determined by measuring the ADP level after phosphorylation of DiC8-PIP2 using a commercially available ADP-Glo kit from Promega. The assay was carried out in white low volume 384 well plates in a final volume of 14 μl at R.T. The assay conditions contained the following: 50 mM Tris buffer pH 7.4, 2.1 mM DTT, 3 mM MgCl2, 0.05% CHAPS, 20 μM ATP, 80 μM DiC8-PIP2 and 1.2 nM PI3Kα, β, γ or 0.6 nM PI3Kδ. Potential inhibitors were made up in DMSO and then diluted in the assay to give a final concentration of not exceeding 1% (v/v) DMSO. A 10-point half-log dilution series of the inhibitors (highest concentration typically 0.1 μM for δ or γ and 33 μM for a or 1) was tested and the pIC50 determined using a 4-parameter logistic equation in a non-linear curve fitting routine. Routinely, inhibitors were pre-incubated with 3 μl of enzyme for 15 min prior to the addition of 2 μl substrate mixture for a further 60 min enzyme reaction. The phosphorylation was stopped with the addition of 3 μl ADP-Glo reagent (stop solution) followed by a 40 min incubation. Prior to detection 6 μl of ADP-Glo Kinase Detection Reagent was added and the plates were read in a micro plate reader using a Luminescence filter. All additions were followed by a short centrifugation step.
Measurement: IC50 = 2055 nM (pChEMBL 5.690000057220459)
Descriptors: MW 608.75, ALogP 3.82, HBA 9, HBD 2, PSA 133.83, QED 0.37
Compound (SMILES): CC(C)Oc1ccc(-c2c[nH]cc2CN(C)CCO)cc1
InChIKey: GNAKYUUZAXUXKB-UHFFFAOYSA-N
Target: Protein arginine N-methyltransferase 6 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96LA8
Assay: Selectivity interaction (Scintillation proximity assay) EUB0000261b PRMT6
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 288.39, ALogP 2.89, HBA 3, HBD 2, PSA 48.49, QED 0.82
Compound (SMILES): CCCN(CCC)CCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: IOJLDPRGTSPRBT-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1D (SINGLE PROTEIN), Homo sapiens
UniProt: P28221
Assay: Binding affinity to 5-HT1DR (unknown origin)
Measurement: Ki = 38 nM (pChEMBL 7.420000076293945)
Descriptors: MW 345.91, ALogP 5.68, HBA 2, HBD 0, PSA 12.47, QED 0.58
Compound (SMILES): Cl.O=C(CCc1ccco1)N[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
InChIKey: KUOBSOJCPUJLSG-CHKFEDFBSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Mus musculus
UniProt: P33534
Assay: Displacement of [3H]-diprenorphine from mouse kappa opioid receptor expressed in CHO cell membranes assessed as inhibition constant incubated for 1.5 hrs by competitive binding assay
Measurement: Ki = 1.52 nM (pChEMBL 8.819999694824219)
Descriptors: MW 464.56, ALogP 2.67, HBA 6, HBD 3, PSA 95.17, QED 0.61
Compound (SMILES): CN1C(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc2ccc(O)cc2)CCCNC(=O)C[C@@H](C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccccc2)C(N)=O)NC(=O)[C@@H]1Cc1ccccc1
InChIKey: RKCXKVATSZRKFH-SPIQOUAPSA-N
Target: Neuropeptide FF receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9GZQ6
Assay: Agonist activity at NPFF1R (unknown origin) expressed in HEK293-A cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins in presence of 3-isobutyl-1-methylxanthine followed by forskolin and compound addition by competitive PKA binding assay
Measurement: EC50 = 436.52 nM (pChEMBL 6.360000133514404)
Descriptors: MW 1138.3
Compound (SMILES): CCCCNCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: PKQCAZLGEGUDLP-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Binding affinity to 5-HT2AR (unknown origin)
Measurement: Ki = 280 nM (pChEMBL 6.550000190734863)
Descriptors: MW 303.83, ALogP 4.91, HBA 2, HBD 1, PSA 21.26, QED 0.73
Compound (SMILES): C[C@@H](c1cc(Cl)cc(Cl)c1)N1CCC(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CC1
InChIKey: SXOAHIZWCZOILH-HNNXBMFYSA-N
Target: Sodium channel protein type 4 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P35499
Assay: Inhibition of full length human Nav1.4 expressed in HEK cells by whole cell voltage clamp analysis
Measurement: IC50 = 3.4 nM (pChEMBL 8.470000267028809)
Descriptors: MW 543.49, ALogP 5.55, HBA 5, HBD 1, PSA 75.71, QED 0.47
Compound (SMILES): CCc1c(C(=O)Nc2cccc(/C=C/C(=O)NO)c2)[nH]c(C)c1C(C)=O
InChIKey: GVORXNGLOKKWIC-CMDGGOBGSA-N
Target: Bromodomain-containing protein 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15059
Assay: Binding affinity to human BRD3 domain 2 assessed as dissociation constant by isothermal titration calorimetry assay
Measurement: Kd > 10000 nM (pChEMBL 5)
Descriptors: MW 355.39, ALogP 2.86, HBA 4, HBD 4, PSA 111.29, QED 0.28
Compound (SMILES): C[C@H](c1ccc(C(F)(F)F)cc1C(F)(F)F)n1cc(NC(=O)c2nnc(-c3ccccn3)s2)cn1
InChIKey: SMOWUSPHXQKMAK-LLVKDONJSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate incubated for 10 mins in presence of NADPH and measured by LC-MS/MS analysis
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 512.44, ALogP 5.7, HBA 7, HBD 1, PSA 85.59, QED 0.35
Compound (SMILES): Cc1nc(Nc2cccc(N3CCNC3=O)n2)sc1-c1cc2c(c(S(=O)(=O)NC3COC3)c1)C(=O)N([C@@H](C)C1CC1)C2
InChIKey: VFBCXKOMIUXVNH-INIZCTEOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Enzymatic Activity Assay : The activity of recombinant human PI3Kγ ((aa144-1102)-6His) and PI3Kα, β, δ (6-His(p110-p85α)) was determined by measuring the ADP level after phosphorylation of DiC8-PIP2 using a commercially available ADP-Glo kit from Promega. The assay was carried out in white low volume 384 well plates in a final volume of 14 μl at R.T. The assay conditions contained the following: 50 mM Tris buffer pH 7.4, 2.1 mM DTT, 3 mM MgCl2, 0.05% CHAPS, 20 μM ATP, 80 μM DiC8-PIP2 and 1.2 nM PI3Kα, β, γ or 0.6 nM PI3Kδ. Potential inhibitors were made up in DMSO and then diluted in the assay to give a final concentration of not exceeding 1% (v/v) DMSO. A 10-point half-log dilution series of the inhibitors (highest concentration typically 0.1 μM for δ or γ and 33 μM for a or 1) was tested and the pIC50 determined using a 4-parameter logistic equation in a non-linear curve fitting routine. Routinely, inhibitors were pre-incubated with 3 μl of enzyme for 15 min prior to the addition of 2 μl substrate mixture for a further 60 min enzyme reaction. The phosphorylation was stopped with the addition of 3 μl ADP-Glo reagent (stop solution) followed by a 40 min incubation. Prior to detection 6 μl of ADP-Glo Kinase Detection Reagent was added and the plates were read in a micro plate reader using a Luminescence filter. All additions were followed by a short centrifugation step.
Measurement: IC50 = 927 nM (pChEMBL 6.03000020980835)
Descriptors: MW 609.73, ALogP 3.22, HBA 9, HBD 3, PSA 145.86, QED 0.34
Compound (SMILES): C[C@H](c1ccc(C(F)(F)F)cc1C(F)(F)F)n1cc(NC(=O)c2nnc(-c3cnccn3)s2)cn1
InChIKey: WOSRMIQXXBKGFN-SNVBAGLBSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate incubated for 10 mins in presence of NADPH and measured by LC-MS/MS analysis
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 513.43, ALogP 5.09, HBA 8, HBD 1, PSA 98.48, QED 0.37
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Protein mono-ADP-ribosyltransferase PARP11 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR21
Assay: Inhibition of human recombinant N-terminal GST-tagged / C-terminal His-tagged PARP11 (8 to 338 end residues) expressed in baculovirus infected Sf9 cells expression system incubated for 1 hr by ELISA assay
Measurement: IC50 = 2281 nM (pChEMBL 5.639999866485596)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4
Compound (SMILES): COCc1nn(Cc2ccc(Cn3cc(F)ccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: ZRUFVDPYHLTYPD-UHFFFAOYSA-N
Target: Serine protease 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P07477
Assay: Determination of Enzyme Selectivity: Human serine protease enzymes plasmin, thrombin and trypsin were assayed for enzymatic activity using an appropriate fluorogenic substrate. Protease activity was measured by monitoring the accumulation of liberated fluorescence from the substrate over 5 minutes. The linear rate of fluorescence increase per minute was expressed as percentage (%) activity. The Km for the cleavage of each substrate was determined by standard transformation of the Michaelis-Menten equation. The compound inhibitor assays were performed at substrate Km concentration and activities were calculated as the concentration of inhibitor giving 50% inhibition (IC50) of the uninhibited enzyme activity (100%).
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 509.51, ALogP 2.9, HBA 8, HBD 1, PSA 100.27, QED 0.35
Compound (SMILES): Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)c1
InChIKey: MSGYSFWCPOBHEV-AWEZNQCLSA-N
Target: Tyrosine-protein kinase receptor UFO (SINGLE PROTEIN), Homo sapiens
UniProt: P30530
Assay: TAM Enzymatic Assay: The kinase assay buffer contained 50 mM HEPES, pH7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% NP-40 and 2 mM DTT. 0.1 ul test compounds dissolved in DMSO were transferred from compound plates to white 384-well assay plates (Greiner LUMITRAC plates). The final concentration of DMSO was 1.25%. Enzyme solutions of 5.1 nM phosphor-Axl, or 0.0625 nM c-Mer (Carna Biosciences, 08-108), or 0.366 nM Tyro3 (Life Technologies, PR7480A) were prepared in assay buffer. A 1 mM stock solution of peptide substrate Biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO: 1 (Quality Controlled Biochemicals, MA) dissolved in DMSO was diluted to 1 uM in assay buffer containing 2000 uM ATP. 4 ul enzyme solution (or assay buffer for the enzyme blank) was added to the appropriate wells in each plate, and then 4 ul/well substrate solution was added to initiate the reaction. The plate was protected from light and incubated at room temperature for 60 min. The reaction was stopped by adding 4 ul detection solution containing 50 mM Tris-HCl, pH7.8, 150 mM NaCl, 0.05% BSA, 45 mM EDTA, 180 nM SA-APC (Perkin Elmer, CR130-100) and 3 nM Eu-W1024 anti-phosphotyrosine PY20 (Perkin Elmer, AD0067). The plate was incubated for 1 h at room temperature, and HTRF (homogenous time resolved fluorescence) signal was measured on a PHERAstar FS plate reader (BMG labtech). Percentage of inhibition was calculated for each concentration and IC50 value was generated from curve fitting with GraphPad Prism software.
Measurement: IC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 507.47, ALogP 3.98, HBA 6, HBD 2, PSA 102.63, QED 0.49
Compound (SMILES): CC(C)c1c2cc(-c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3F)ccc2nn1C
InChIKey: LLFOBMRPWNABCB-UHFFFAOYSA-N
Target: CDK6/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24385
Assay: Inhibition of CDK6/Cyclin D1 (unknown origin) transfected in HEK293 cells by NanoBRET assay
Measurement: IC50 = 60.3 nM (pChEMBL 7.21999979019165)
Descriptors: MW 446.53, ALogP 3.84, HBA 8, HBD 2, PSA 83.79, QED 0.48
Compound (SMILES): C[C@H](CC[C@](C)(O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
InChIKey: BVBRUQYHUXKZMQ-JNVAYQLDSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 (unknown origin)
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 456.63, ALogP 7.05, HBA 2, HBD 2, PSA 40.46, QED 0.45
Compound (SMILES): CC(C)N1CCOc2c(F)cc(-c3nc(Nc4ccc(C5CCN(C)CC5)cn4)ncc3F)cc21
InChIKey: YZSCPLGKKMSBMV-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Activity Assay: PI3Kδ: Briefly, this assay was conducted in buffer (Tris-HCl 40 mM (pH7.5), Orthovanadate 3 mM, MgCl2 20 mM, DTT 2 mM, CHAPS 0.05%, DMSO 1%). PI3Kδ kinase was added to the reaction solution and mixed gently. The test compounds in 100% DMSO (at specific solutions) were mixed with the kinase reaction mixture to achieve the final compounds at pre-defined concentrations (e.g., range—0.5 nM to 100 μM) by Acoustic technology (Echo550; nanoliter range). After incubating for 10 min at room temp, ATP was added into the reaction mixture to initiate the reaction followed by a 30-min incubation at 30° C. After quenching the reaction with ADP-Glo reagent, the plates were incubated for 40 min. The Detection Mixture was added, and the plate was incubated for an additional 30 min. At the end of incubation, luminescence was measured. For data analysis, the luminescence was converted into μM ADP production based on ADP standard curves.
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 480.56, ALogP 4.98, HBA 7, HBD 1, PSA 66.41, QED 0.55
Compound (SMILES): CC(C)CCN[C@@H]1CCc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2C1
InChIKey: DVFCRTGTEXUFIN-GFCCVEGCSA-N
Target: Tyrosine-protein phosphatase non-receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P17706
Assay: Inhibition of full-length human recombinant PTPN2 incubated for 20 mins by mobile shift assay
Measurement: IC50 = 1.8 nM (pChEMBL 8.739999771118164)
Descriptors: MW 385.46, ALogP 1.21, HBA 5, HBD 3, PSA 98.74, QED 0.71
Compound (SMILES): CO[C@@H]1CCN(c2nccc(Nc3cc4c(C(C)C)ccc(N5C[C@H](CS(C)(=O)=O)[C@H]5C)c4cn3)n2)C[C@@H]1F
InChIKey: LIMFPAAAIVQRRD-BCGVJQADSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of N-terminal GST tagged recombinant human EGFR ex19del(746 to 750)/T790M mutant (668 to end residues) expressed in baculovirus infected Sf9 insect cells expression system using 5-FAM-EEPLYINSFPAKKK-CONH peptide as substrate preincubated for 10 mins followed by peptide substrate addition in presence of ATP
Measurement: IC50 = 0.8 nM (pChEMBL 9.100000381469727)
Descriptors: MW 556.71, ALogP 4.32, HBA 9, HBD 1, PSA 100.55, QED 0.43
Compound (SMILES): O=C1COc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
InChIKey: PMKMNTBZJOXTJW-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Binding Assay: Receptor Source: Human Cortex  Radioligand: [3H]-Ketanserin (60-90 Ci/mmol)  Control Compound: Ketanserin  Incubation Conditions: The reactions were carried out in 50 mM TRIS-HCl (pH 7.6) at room temperature for 90 minutes. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters was determined and compared to control values in order to ascertain any interactions of test compounds with the serotonin-5HT2A binding site (Literature Reference: Leysen, J. E. et al. Mol. Pharmacol. 1982, 21, 301-314; Martin, G. R. and Humphrey, P. P. A. Neuropharmacol. 1994, 33(3/4), 261-273.)
Measurement: Ki = 58.5 nM (pChEMBL 7.230000019073486)
Descriptors: MW 450.37, ALogP 4.31, HBA 5, HBD 1, PSA 54.04, QED 0.64
Compound (SMILES): COC[C@H](NC(=O)c1ccn(S(C)(=O)=O)c1)C(=O)Nc1nc(-c2cccc(N3C[C@@H](C)O[C@@H](C)C3)n2)cs1
InChIKey: JBLQNFBXKOAIHG-FCEWJHQRSA-N
Target: Cytochrome P450 2C8 (SINGLE PROTEIN), Homo sapiens
UniProt: P10632
Assay: Inhibition of CYP2C8 (unknown origin)
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 562.67, ALogP 1.81, HBA 11, HBD 2, PSA 144.75, QED 0.4
Compound (SMILES): Oc1ccc2c3c(cnc2c1)-c1ccc(C(F)(F)F)cc1O[C@@H]3c1ccc(OCCN2CC(CF)C2)cc1
InChIKey: UVBQMXOKKDCBJN-MUUNZHRXSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Induction of ERalpha Y537N mutant degradation in human MCF cells high content imaging assay
Measurement: IC50 = 9.6 nM (pChEMBL 8.020000457763672)
Descriptors: MW 524.51, ALogP 6.39, HBA 5, HBD 1, PSA 54.82, QED 0.3
Compound (SMILES): Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: TVGAHWWPABTBCX-UHFFFAOYSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of human CYP2C19
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 431.5, ALogP 3.56, HBA 9, HBD 1, PSA 99.75, QED 0.5
Compound (SMILES): C[C@@H](N)c1cc(Cl)ccc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
InChIKey: BHKKSKOHRFHHIN-MRVPVSSYSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of hERG
Measurement: IC50 = 21000 nM (pChEMBL 4.679999828338623)
Descriptors: MW 334.83, ALogP 3.11, HBA 4, HBD 3, PSA 79.6, QED 0.64
Compound (SMILES): CCc1cc2ncc(CN3CCN(c4ccc(C(=O)NC)nc4)CC3)cc2[nH]c1=O
InChIKey: WQAVGRAETZEADU-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP-1 (unknown origin) binding to DNA assessed as DNA trapping activity
Measurement: IC50 = 0.65 nM (pChEMBL 9.1899995803833)
Descriptors: MW 406.49, ALogP 1.56, HBA 6, HBD 2, PSA 94.22, QED 0.67
Compound (SMILES): CNC(=O)c1ccc(N2CCN(Cc3ccc4nc(C)c(=O)[nH]c4c3F)CC2)c(F)n1
InChIKey: WXRCLFFPZXJCLS-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP1 (unknown origin) measured after 2 hrs by ELISA
Measurement: IC50 = 870 nM (pChEMBL 6.059999942779541)
Descriptors: MW 428.44, ALogP 1.59, HBA 6, HBD 2, PSA 94.22, QED 0.61
Compound (SMILES): Cc1cnc(-c2cc(O[C@@H]3CCOC3)cc(C(=O)N[C@H](C)c3cnc(C(F)(F)F)nc3)c2)s1
InChIKey: GTQPEQGDLVSFJO-CXAGYDPISA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: CYP Inhibition Assay: Human liver microsomes (pooled, >30 male and female donors) were incubated with individual CYP isoform-selective standard probes (phenacetin for CYP1A2, amodiquine for CYP2C8, diclofenac for CYP2C9, dextromethorphan for CYP2D6 and midazolam for CYP3A4) in the absence and presence of increasing concentrations of the test compound in order to compare the extent of formation of the respective metabolite. In addition, a set of incubation in the absence of test compound was used as a negative control. Furthermore, the inhibitory potency of standard inhibitors was included as positive controls (fluvoxamine for CYP1A2, montelukast for CYP2C8, sulfaphenazole for CYP2C9, fluoxetine for CYP2D6, ketoconazole for CYP3A4 and mibefradil for CYP3A4-preincubation). Incubation conditions (protein and probe substrate concentration, incubation time) were optimised with regard to linearity and metabolite turnover. Incubation medium consisted of 50 mM potassium phosphate buffer (pH 7.4) containing 1 mM EDTA, NADPH regenerating system (1 mM NADP, 5 mM glucose 6-phosphate, glucose 6-phosphate dehydrogenase (1.5 U/mL). Sequential dilutions and incubations were performed on a Genesis Workstation (Tecan, Crailsheim, FRG) in 96-well plates at 37° C. A final incubation volume of 200 μL was used. Reactions were stopped by addition of 100 μL acetonitrile containing the respective internal standard. Precipitated proteins were removed by centrifugation of the well plate, supernatants were combined and analyses were performed by LC-MS/MS. The LC-MS/MS quantification of the metabolites paracetamol (CYP1A2), desethylamodiaquine (CYP2C8), 4-hydroxydiclofenac (CYP2C9), dextrorphan (CYP2D6), and 1-hydroxymidazolam (CYP3A4) was performed with a PE SCIEX API 3000 LC/MS/MS system (Applied Biosystems, MDS Sciex, Concord, Ontario, Canada).
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 478.5, ALogP 4.59, HBA 7, HBD 1, PSA 86.23, QED 0.56
Compound (SMILES): NCCCC[C@H](NC(=O)C1CCCC1)C(=O)COc1c(F)ccc(F)c1F
InChIKey: OLIMBXKACVCIMM-HNNXBMFYSA-N
Target: Cathepsin K (SINGLE PROTEIN), Homo sapiens
UniProt: P43235
Assay: Inhibition of Lysine Gingipain: The capacities of compounds of the present invention to inhibit the activity of lysine gingipain were measured in a fluorogenic assay similar to those described by Barret (Biochemical Journal. 1980, 187(3), 909). The specific assay conditions were as follows. Buffer: pH=7.5, 100 mM Tris-HCl, 75 mM NaCl, 2.5 mM CaCl2), 10 mM cysteine, 1% DMSO after all additions. Protein: 0.1 nM Kgp, isolated from culture of Porphyromonas gingivalis, as described by Pike et al. (J. Biol. Chem. 1994, 269(1), 406), and Potempa and Nguyen (Current Protocols in Protein Science. 2007, 21.20.1-21.20.27). Fluorogenic substrate: 10 μM Z-His-Glu-Lys-MCA. Time=90 minutes. Temperature=37° C. Each compound: 10 concentrations, starting at either 100 μM or 100 nM, with lower concentrations generated by serial 3-fold dilutions. By testing a range of concentrations for each compound, the concentration required to inhibit the activity of lysine gingipain by 50% (the IC50) was determined. Under the described assay conditions, the signal-to-noise ratio was excellent, and the Z factor was greater than 0.6. Compounds in Table 1 were tested, as well as the compounds set forth in Table 2 below.The capacities of compounds of the present invention to inhibit the activity of cathepsins B, H, K, L, and S were measured in similar assays. Boc-Leu-Arg-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin B assay. L-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin H assay. Z-Phe-Arg-AMC (10 μM) in HEPES buffer (50 mM, pH 7.4) containing DTT (2.5 mM) and EDTA (1 mM) was used for the Cathepsin K assay. Z-Phe-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin L assay. Z-Leu-Arg-AMC (10 μM) in sodium acetate buffer (25 mM, pH 4.5) containing DTT (2.5 mM) and NaCl (50 mM) was used for the Cathepsin S assay.
Measurement: IC50 = 117 nM (pChEMBL 6.929999828338623)
Descriptors: MW 386.41, ALogP 2.86, HBA 4, HBD 2, PSA 81.42, QED 0.48
Compound (SMILES): CC(=O)N1CCN([C@H]2CCC[C@@H](NC(=O)c3cc4c(F)ccc(C)c4[nH]3)C2)CC1
InChIKey: PGNLXEBQMQHFNK-SJORKVTESA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 in human liver microsomes using (s)-mephenytoin as substrate preincubated for 5 mins followed by NADPH addition measured after 20 mins by LC-MS/MS analysis
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 400.5, ALogP 2.82, HBA 3, HBD 2, PSA 68.44, QED 0.83
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 in human liver microsomes assessed as reduction in 4-hydroxymephenytoin metabolite formation incubated for 30 mins in presence of NADPH by LC-MS/MS analysis
Measurement: IC50 > 25000 nM (pChEMBL 4.6020002365112305)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): CC1(C)Cn2nc(-c3ccc(F)cn3)c(-c3ccnc4[nH]ncc34)c2CO1
InChIKey: WZMIWVZGYMKUDV-UHFFFAOYSA-N
Target: Cytochrome P450 2D6 (SINGLE PROTEIN), Homo sapiens
UniProt: P10635
Assay: Inhibition of CYP2D6 in human liver microsomes incubated for 10 mins in presence of NADPH by LC-MS/MS analysis
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 364.38, ALogP 3.33, HBA 6, HBD 1, PSA 81.51, QED 0.59