lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COC(=O)C1(C/C=C/c2ccccc2)/C(=C/C=O)O[C@@H]2CC(=O)N21
InChIKey: VWSIAIDFEKNQNE-PULDSNBPSA-N
Target: Beta-lactamase TEM (SINGLE PROTEIN), Bacteria
UniProt: P62593
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 4268.3 nM (pChEMBL 5.369999885559082)
Descriptors: MW 327.34, ALogP 1.67, HBA 5, HBD 0, PSA 72.91, QED 0.36
Compound (SMILES): O=C(O)/C=C1\O[C@@H]2CC(=O)N2C1(C/C=C/c1ccccc1)C(=O)OCc1ccccc1
InChIKey: TXPJIXCYUFODBL-WWTCDDSASA-N
Target: Beta-lactamase SHV-1 (SINGLE PROTEIN), Escherichia coli
UniProt: P0AD63
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 9317.9 nM (pChEMBL 5.03000020980835)
Descriptors: MW 419.43, ALogP 3.13, HBA 5, HBD 1, PSA 93.14, QED 0.42
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Cytoplasmic tyrosine-protein kinase BMX (SINGLE PROTEIN), Homo sapiens
UniProt: P51813
Assay: Inhibition of BMX (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 1.8 nM (pChEMBL 8.739999771118164)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COC(=O)C1(C/C=C/c2ccccc2)/C(=C/C(=O)O)O[C@@H]2CC(=O)N21
InChIKey: FJEAGJSMLOQFME-MJSMECKXSA-N
Target: Beta-lactamase SHV-1 (SINGLE PROTEIN), Escherichia coli
UniProt: P0AD63
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 642.3 nM (pChEMBL 6.190000057220459)
Descriptors: MW 343.34, ALogP 1.56, HBA 5, HBD 1, PSA 93.14, QED 0.5
Compound (SMILES): O=C1OC(CI)C/C1=C1/O[C@@H]2CC(=O)N2C1C(=O)OCc1ccccc1
InChIKey: ROBNSNBYRBBNOO-RZFORLEUSA-N
Target: Beta-lactamase SHV-1 (SINGLE PROTEIN), Escherichia coli
UniProt: P0AD63
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 0.8 nM (pChEMBL 9.100000381469727)
Descriptors: MW 469.23, ALogP 1.69, HBA 6, HBD 0, PSA 82.14, QED 0.22
Compound (SMILES): Cc1nc(C(C)Nc2ncc(F)c(N3C(=O)OC[C@@H]3[C@@H](C)O)n2)oc1-c1ccc(Cl)cc1
InChIKey: HLHUIGPXIQCWLI-ZLXOECBPSA-N
Target: Isocitrate dehydrogenase [NADP] cytoplasmic (SINGLE PROTEIN), Homo sapiens
UniProt: O75874
Assay: Mutant IDH1 Biochemical Assay: LC-MS Detection of 2-HG: Mutant IDH1 R132H catalytic activity was monitored using the quantitative liquid chromatography/mass spectrometry (LC-MS) detection of 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.More specifically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Costar, Cat. No. 781201) using a final reaction volume of 30 μL and the following assay buffer conditions: 50 mM HEPES pH 7.4, 10 mM MgCl2, 50 mM KCl, 1 mM DTT, 0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.The final reaction mixture contained 3.3% DMSO and inhibitors with concentrations ranging 0.02-50 μM. The IDH1 enzyme was used at a final concentration of 0.25 nM. Following 45 minutes incubation, the reaction mixtures were quenched by the addition of 10 μL of 16% formic acid containing 800 nM of 5-carbon labeled 13C-2-HG). The protein was then precipitated by the addition of 2.5 volumes of acetonitrile followed by centrifugation (3000×g, 20 minutes). The concentration of 2-HG in the resulting supernatants was measured by LC-MS (see below).LC-MS method. Reaction mixture supernatants were submitted to chromatographic separation on a BiobasicAX column (2.1 mm×20 mm, 5 μm particle, Thermo Scientific Inc.). The chromatographic mobile phases were A) 25 mM ammonium biocarbonate and B) acetonitrile (0.1% ammonium hydroxide). Nicotinamide was eluted at 1 ml/min using a 85-5% B gradient over 0.9 minutes (Agilent 1200SL LC system, Thermofisher LX-4 autosampler) and analyzed by multiple reaction monitoring (MRM) on a API4000 QTrap mass spectrometer (ABSciex, Framingham, Mass.) in the positive electrospray ionization (ESI+) mode. The mass transition for 2-HG and 13C-2-HG were 147→129 and 152→134, respectively. The relative responses (2-HG/13C-2-HG) were measured at varied inhibitor concentrations and used to calculate inhibitory IC50 values (normalized IC50 regression curves).
Measurement: IC50 = 2583 nM (pChEMBL 5.590000152587891)
Descriptors: MW 461.88, ALogP 4.11, HBA 8, HBD 2, PSA 113.61, QED 0.56
Compound (SMILES): N[C@]12CCC[C@H](C[C@H](n3c(=O)c(C(=O)O)nc4ccccc43)C1)N2C1CC2CCCC(C2)C1
InChIKey: HOWIQHYXNHBQBA-JHITZODSSA-N
Target: Opioid growth factor receptor-like protein 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q5TC84
Assay: ORL-1 GTPgammaS Binding Assay: Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish) followed by homogenization with a tissue grinder/Teflon pestle. Membranes were collected by centrifugation at 30,000xg for 15 min at 4° C., and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/mL. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as a standard. Aliquots of the ORL-1 receptor membranes were stored at -80° C. Functional binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 ug/uL ORL-1 membrane protein, 10 ug/mL saponin, 3 uM GDP and 0.20 nM [35S]G IPgammaS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.
Measurement: EC50 = 545 nM (pChEMBL 6.260000228881836)
Descriptors: MW 450.58, ALogP 3.91, HBA 6, HBD 2, PSA 101.45, QED 0.74
Compound (SMILES): CCOP(=O)(OCC)[C@@H](Nc1nc2ccc(OC)cc2s1)c1ccc(O)c(C(=O)OC)c1
InChIKey: QQNBEGHUFQPJQY-LJQANCHMSA-N
Target: Amyloid beta-binding alcohol dehydrogenase (SINGLE PROTEIN), Homo sapiens
UniProt: Q2L8D9
Assay: Assay of ABAD Enzymatic Activity: The assay for the inhibition of reduction of S-acetoacetyl-CoA (SAAC) by ABAD was carried out with ABAD (418 ng/ml), SAAC (172 μM), NADH (102 μM), and different concentrations of inhibitors (from 0 to 1000 μM) in 93 mM potassium phosphate buffer (pH 7.3). Before the assay, all the assay components except SAAC were pre-incubated for 5 minutes, and the reaction started with the addition of SAAC into the reaction mix. The reaction was carried out for a total 6 minutes at room temperature under steady-state conditions, and the decrease of NADH absorbance at 340 nm was determined every 10 seconds. Kinetic data were analyzed by PRISM (Scitech, San Diego, Calif.) to determine IC50 values and Ki. One unit of enzyme activity was defined as that which converted 1.0 μmol of substrate to product per minute.
Measurement: Ki = 2800 nM (pChEMBL 5.550000190734863)
Descriptors: MW 480.48, ALogP 5.17, HBA 10, HBD 2, PSA 116.21, QED 0.3
Compound (SMILES): C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1
InChIKey: JVOJDDPNCSLEDA-HXUWFJFHSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of human ERG by automated patch clamp assay
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 447.42, ALogP 3.58, HBA 6, HBD 3, PSA 103.37, QED 0.55
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Tyrosine-protein kinase BTK (SINGLE PROTEIN), Homo sapiens
UniProt: Q06187
Assay: Inhibition of BTK in human whole blood assessed as reduction in cell surface CD69 expression preincubated for 1 hr followed by stimulation with anti-CD79b for 3 hrs by immunostaining analysis
Measurement: IC50 = 30 nM (pChEMBL 7.519999980926514)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4nc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c4c3)cc2)[nH]1)[C@@H](C)OC
InChIKey: PEOWHPQZIHJCOF-HJANNDIRSA-N
Target: Nonstructural protein 5A (SINGLE PROTEIN), Hepatitis C virus
UniProt: Q5L478
Assay: Transient Replicon Assay: In a transient set-up, a Huh-7 lunet hepatoma cell line was transiently transfected with an autonomously replicating RNA encoding a bi-cistronic expression construct. This construct comprises a firefly luciferase reporter gene preceding the NS3-NS5B subgenomic region of HCV (genotype 1a H77 or 1b Con1). Translation of the HCV subgenomic region is mediated by an internal ribosome entry site of encephalomyocarditis virus. The construct is furthermore flanked by 5' and 3' untranslated regions of HCV (genotype 1a H77 or 1b Con 1, respectively), which allow for replication of the RNA. In addition to the wild-type constructs, site-directed mutations were introduced into the transient HCV genotype 1b replicon in the gene encoding for the non-structural protein 5A (NS5A). More precisely, amino acid residues 28, 30, 31 and 93 in NS5A were independently altered. Cells were plated in 384 well plates in the presence of test and control compounds, which were added in various concentrations. Following an incubation of two days, replication of the HCV subgenomic replicon RNA was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux™ ultraHTS microplate imager). HCV subgenomic replicon containing cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound was monitored, enabling a dose-response curve for each test compound.
Measurement: EC50 = 2.882 nM (pChEMBL 8.539999961853027)
Descriptors: MW 744.85, ALogP 4.47, HBA 10, HBD 4, PSA 193.1, QED 0.16
Compound (SMILES): CC(C)Oc1ccc(-c2nn([C@H](C)c3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1F
InChIKey: IUVCFHHAEHNCFT-MRXNPFEDSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Binding affinity to PI3Kdelta (unknown origin) assessed as dissociation constant
Measurement: Kd > 6.2 nM (pChEMBL 8.208000183105469)
Descriptors: MW 571.56, ALogP 6.66, HBA 8, HBD 1, PSA 109.06, QED 0.24
Compound (SMILES): CO[C@]12CC[C@@]3(C[C@@H]1COc1ccc(-n4ccnc4)cc1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1C)[C@H]2O5
InChIKey: NILYQWCAXZIPIK-SNYCAXESSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: Functional Assay: Functional [35S]GTPgammaS binding assays were conducted as follows. kippa opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 ug/ul kippa membrane protein (in-house), 10 ug/mL saponin, 3 uM GDP and 0.20 nM [35S]GTPgammaS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ul/well) was transferred to 96-shallow well polypropylene plates containing 10 ul of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25° C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 2001 ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C. for 2-3 hours.
Measurement: EC50 = 129.34 nM (pChEMBL 6.889999866485596)
Descriptors: MW 499.61, ALogP 4.1, HBA 7, HBD 1, PSA 68.98, QED 0.57
Compound (SMILES): O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1
InChIKey: OOJUYQYOGSIFSN-QGZVFWFLSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Cellular Proliferation Assay: Test compounds were resuspended in DMSO at a concentration of 10 mM. A serial three-fold dilution of each compound with DMSO was performed in 384-well plates using the Janus Liquid Dispenser (PerkinElmer). Compound was delivered to the assay plates containing 2500 cells in a 50 μL volume via Acoustic delivery from an ATS-100 (EDC). For Ba/F3-BCR-ABL1-WT cell assays, 2 nL of each compound dilution was transferred to the assay plate for final assay concentrations of 0.4 μM, 0.13 μM, 0.044 μM, 0.015 μM, 0.005 μM, 0.001 μM, 0.00033 μM, 0.00011 μM, 0.000037 μM, 0.000012 μM. For Ba/F3-WT and Ba/F3-BCR-ABL1-T315I cell assays, 50 nL of each compound dilution was transferred to the assay plate for final assay concentrations of 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.041 μM, 0.014 μM, 0.0046 μM, 0.0015 μM, 0.00051 μM.Cells were incubated at 37° C. in a humidified environment with 5% car
Measurement: IC50 = 24 nM (pChEMBL 7.619999885559082)
Descriptors: MW 478.47, ALogP 4.72, HBA 6, HBD 2, PSA 78.35, QED 0.41
Compound (SMILES): C[C@@H](Oc1cc(-c2cnn(C3CC4(CCNCC4)C3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
InChIKey: MXQDRRGPOHEUMT-CQSZACIVSA-N
Target: ALK tyrosine kinase receptor (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UM73
Assay: Inhibition Assay: The inhibitory activities of compounds of Formula I were assay at Reaction Biology Corporation, One Great Valley Parkway, Malvern, Pa., USA. Human ALK and cMet enzymes were used and the substrate was a peptide substrate, poly[Glu:Tyr] (4:1) at a concentration of 0.2 mg/ml. The ATP concentration for the assay was 10 uM and Staurosporine was used as a standardwith an IC50 of 2.3 nM, and 75 nM, respectively for ALK and cMet.
Measurement: IC50 = 1.5 nM (pChEMBL 8.819999694824219)
Descriptors: MW 490.41, ALogP 5.82, HBA 6, HBD 2, PSA 77.99, QED 0.44
Compound (SMILES): NC(=O)C1CCC(N[C@H]2C[C@@H]2c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
InChIKey: WVVHNLMQBRBRGZ-DTYDVHMXSA-N
Target: Lysine-specific histone demethylase 1A (SINGLE PROTEIN), Homo sapiens
UniProt: O60341
Assay: Biological Assay: The compounds of the invention can be tested for their ability to inhibit LSD1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc (catalog reference number 50100: human recombinant LSD1, GenBank accession no. NM_015013, amino acids 158-end with N-terminal GST tag, MW: 103 kDa). In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di-methylated H3-K4 peptide (Anaspec) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H2O2 produced during the catalytic process, using the Amplex Red hydrogen peroxide/peroxidase assay kit (Invitrogen).Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of at least eight 3-fold serial dilutions of the respective inhibitor (e.g., from 0 to 75 uM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, KM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 5 extra minutes at room temperature in the dark. A 1 uM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor. The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The IC50 value of each inhibitor was calculated with GraphPad Prism Software.
Measurement: Ki = 50 nM (pChEMBL 7.300000190734863)
Descriptors: MW 403.45, ALogP 4.26, HBA 3, HBD 2, PSA 68.01, QED 0.78
Compound (SMILES): COc1ccc2c3c1O[C@H]1[C@@]4(OC)CC[C@@]5(C[C@@H]4COCc4c(C)noc4C)[C@@H](C2)N(C)CC[C@]315
InChIKey: YSFWOXQJZZJOCO-SDNJBTIHSA-N
Target: Delta-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41143
Assay: Functional Assay: Functional [35S]GTPgammaS binding assays were conducted as follows. Delta opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 ug/ul delta membrane protein (Perkin Elmer, Shelton, Conn.), 10 ug/mL saponin, 3 uM GDP and 0.20 nM [35S]GTPgammaS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ul/well) was transferred to 96-shallow well polypropylene plates containing 10 ul of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25° C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 ul ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C. for 1-2 hours.
Measurement: EC50 = 841.4 nM (pChEMBL 6.079999923706055)
Descriptors: MW 480.61, ALogP 3.96, HBA 7, HBD 0, PSA 66.19, QED 0.62
Compound (SMILES): CC12C[C@H]3C[C@@H](N4[C@@H]5CCC[C@H]4C[C@@H](n4c(=O)c(N6CC[C@H]6C(=O)O)nc6ccccc64)C5)C[C@@H]1C[C@@H]2C3
InChIKey: YSMGRXHMHZXHMK-PPGQYDOQSA-N
Target: Mu-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P35372
Assay: In Vitro Mu-Opioid Receptor Functional Assay: [35S]GTPγS functional assays were conducted using freshly thawed membranes expressing human μ-receptors. Assay reactions were prepared by sequentially adding the following reagents to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice (final concentrations indicated): membrane protein (0.026 mg/mL), saponin (10 mg/mL), GDP (3 mM) and [35S]GTPγS (0.20 nM; NEN). The prepared membrane solution (190 μL/well) was transferred to 96-shallow well polypropylene plates containing 10 μL of 20× concentrated stock solutions of the agonist DAMGO ([D-Ala2, N-methyl-Phe4 Gly-o15]-enkephalin) prepared in dimethyl sulfoxide (DMSO). Plates were incubated for 30 min at about 25 °C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard, Meriden, Conn.) using a 96-well tissue harvester (Brandel, Gaithersburg, Md.) followed by three filtration washes with 200 μL of ice-cold wash buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50 °C. for 2-3 hr. BetaScint scintillation cocktail (Wallas, Turku, Finland) was added (50 μL/well) and plates were counted using a Packard Top-Count for 1 min/well.
Measurement: EC50 = 363 nM (pChEMBL 6.440000057220459)
Descriptors: MW 516.69, ALogP 4.83, HBA 6, HBD 1, PSA 78.67, QED 0.63
Compound (SMILES): C[C@@H]1c2nnc(-c3cccc(O)n3)n2CCN1C(=O)c1ccc(-c2cccs2)cc1
InChIKey: JSJMFCNSTAYAHE-CQSZACIVSA-N
Target: Transcriptional regulator ERG (SINGLE PROTEIN), Homo sapiens
UniProt: P11308
Assay: hERG Inhibition Assay: The human Ether-a-go-go Related Gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr) which is involved in cardiac repolarisation. IKr current inhibition has been shown to elongate the cardiac action potential, a phenomenon associated with increased risk of arrhythmia. IKr current inhibition accounts for the vast majority of known cases of drug-induced QT-prolongation. A number of drugs have been withdrawn from late stage clinical trials due to these cardiotoxic effects, therefore it is important to identify inhibitors early in drug discovery.The hERG inhibition study aims at quantifying the in vitro effects of compounds of the invention on the potassium-selective IKr current generated in normoxic conditions in stably transfected HEK 293 cells with the human ether-a-go-go-related gene (hERG).Whole-cell currents (acquisition by manual patch-clamp) elicited during a voltage pulse were recorded in baseline conditions and following application of tested compounds (5 minutes of exposure). The concentrations of tested compounds (0.3 μM; 3 μM; 10 μM; 30 μM) reflect a range believed to exceed the concentrations at expected efficacy doses in preclinical models.The pulses protocol applied is described as follow: the holding potential (every 3 seconds) was stepped from −80 mV to a maximum value of +40 mV, starting with −40 mV, in eight increments of +10 mV, for a period of 1 second. The membrane potential was then returned to −55 mV, after each of these incremented steps, for 1 second and finally repolarized to −80 mV for 1 second.The current density recorded were normalized against the baseline conditions and corrected for solvent effect and time-dependent current run-down using experimental design in test compound free conditions.Inhibition curves were obtained for compounds and the concentrations which decreased 50% of the current density determined in the baseline conditions (IC50) were determined. All compounds for which the IC50 value is above 10 M are not considered to be potent inhibitors of the hERG channel whereas compounds with IC50 values below 1 μM are considered potent hERG channel inhibitors.
Measurement: IC50 = 20000 nM (pChEMBL 4.699999809265137)
Descriptors: MW 417.49, ALogP 3.99, HBA 7, HBD 1, PSA 84.14, QED 0.54
Compound (SMILES): COc1ccc2nc(N[C@@H](c3ccc(O)cc3)P(=O)(OC)OC)sc2c1
InChIKey: SMXXEEKTXGMORR-MRXNPFEDSA-N
Target: Amyloid beta-binding alcohol dehydrogenase (SINGLE PROTEIN), Homo sapiens
UniProt: Q2L8D9
Assay: Inhibition Assay: To perform kinetic analyses of the binding of phosphonate derivatives to ABAD, the BIACORE 3000 instrument (based on surface plasmon resonance [SPR] technology) was used.
Measurement: IC50 = 52700 nM (pChEMBL 4.28000020980835)
Descriptors: MW 394.39, ALogP 4.61, HBA 8, HBD 2, PSA 89.91, QED 0.57
Compound (SMILES): CO[C@]12CC[C@@]3(C[C@@H]1COCc1ccccc1)[C@H]1Cc4ccc(C(N)=O)c5c4[C@@]3(CCN1C)[C@H]2O5
InChIKey: YWZUTHYBZDSTKA-IPRXQQHWSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: Functional Assay: Functional [35S]GTPgammaS binding assays were conducted as follows. kippa opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 ug/ul kippa membrane protein (in-house), 10 ug/mL saponin, 3 uM GDP and 0.20 nM [35S]GTPgammaS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ul/well) was transferred to 96-shallow well polypropylene plates containing 10 ul of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25° C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 2001 ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C. for 2-3 hours.
Measurement: EC50 = 13.27 nM (pChEMBL 7.880000114440918)
Descriptors: MW 474.6, ALogP 3.45, HBA 5, HBD 1, PSA 74.02, QED 0.69
Compound (SMILES): O=C(O)/C=C1\O[C@@H]2CC(=O)N2C1(C/C=C/c1ccccc1)C(=O)OCc1ccccc1
InChIKey: TXPJIXCYUFODBL-WWTCDDSASA-N
Target: Beta-lactamase TEM (SINGLE PROTEIN), Bacteria
UniProt: P62593
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 45684.4 nM (pChEMBL 4.340000152587891)
Descriptors: MW 419.43, ALogP 3.13, HBA 5, HBD 1, PSA 93.14, QED 0.42
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 368 nM (pChEMBL 6.429999828338623)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COC(=O)C1(C/C=C/c2ccccc2)/C(=C/C(=O)O)O[C@@H]2CC(=O)N21
InChIKey: FJEAGJSMLOQFME-MJSMECKXSA-N
Target: Beta-lactamase TEM (SINGLE PROTEIN), Bacteria
UniProt: P62593
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 407.6 nM (pChEMBL 6.389999866485596)
Descriptors: MW 343.34, ALogP 1.56, HBA 5, HBD 1, PSA 93.14, QED 0.5
Compound (SMILES): O=C1OC(CI)C/C1=C1/O[C@@H]2CC(=O)N2C1C(=O)OCc1ccccc1
InChIKey: ROBNSNBYRBBNOO-RZFORLEUSA-N
Target: Beta-lactamase TEM (SINGLE PROTEIN), Bacteria
UniProt: P62593
Assay: Cell Free Inhibition Assay: The inhibitory concentrations (IC50, [uM]) of the beta -lactamase inhibitors against purified TEM-1, SHV-1 and AmpC beta -lactamases are assessed by determining the concentration of inhibitor at which 50% of the nitrocefin hydrolysis is inhibited by the particular enzyme. Assays are performed with beta -lactamases expressed in the pET system (Novagen, San Diego, Calif.) without signal peptides. They contain an N-terminal hexa-Histidine tag that is used for purification on Ni-NTA (Qiagen, Hilden, Germany). The compounds are prepared as 50 mM stocks in DMSO and diluted into buffer P1 (50 mM phosphate, pH 7) to a final concentration of 10% DMSO. All further dilutions are done in P2 (P1 with 10% DMSO). Enzyme and compound dilutions are pre-incubated for 10 min at 37 C. and the reaction is started with the addition of pre-warmed (37 C.) nitrocefin at a final concentration of 50 mM. The change in absorption at 490 nm is followed at 37 C. for 10 min with 30 s intervals.
Measurement: IC50 = 1.7 nM (pChEMBL 8.770000457763672)
Descriptors: MW 469.23, ALogP 1.69, HBA 6, HBD 0, PSA 82.14, QED 0.22
Compound (SMILES): CCOP(=O)(OCC)[C@@H](Nc1nc2ccc(OC)cc2s1)c1ccc(O)c(C(=O)OC)c1
InChIKey: QQNBEGHUFQPJQY-LJQANCHMSA-N
Target: Amyloid beta-binding alcohol dehydrogenase (SINGLE PROTEIN), Homo sapiens
UniProt: Q2L8D9
Assay: Assay of ABAD Enzymatic Activity: The assay for the inhibition of reduction of S-acetoacetyl-CoA (SAAC) by ABAD was carried out with ABAD (418 ng/ml), SAAC (172 μM), NADH (102 μM), and different concentrations of inhibitors (from 0 to 1000 μM) in 93 mM potassium phosphate buffer (pH 7.3). Before the assay, all the assay components except SAAC were pre-incubated for 5 minutes, and the reaction started with the addition of SAAC into the reaction mix. The reaction was carried out for a total 6 minutes at room temperature under steady-state conditions, and the decrease of NADH absorbance at 340 nm was determined every 10 seconds. Kinetic data were analyzed by PRISM (Scitech, San Diego, Calif.) to determine IC50 values and Ki. One unit of enzyme activity was defined as that which converted 1.0 μmol of substrate to product per minute.
Measurement: Kd = 256 nM (pChEMBL 6.590000152587891)
Descriptors: MW 480.48, ALogP 5.17, HBA 10, HBD 2, PSA 116.21, QED 0.3
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Tyrosine-protein kinase Blk (SINGLE PROTEIN), Homo sapiens
UniProt: P51451
Assay: Inhibition of BLK (unknown origin)
Measurement: IC50 = 101 nM (pChEMBL 7)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4nc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c4c3)cc2)[nH]1)[C@@H](C)OC
InChIKey: PEOWHPQZIHJCOF-HJANNDIRSA-N
Target: Nonstructural protein 5A (SINGLE PROTEIN), Hepatitis C virus
UniProt: Q5L478
Assay: Transient Replicon Assay: In a transient set-up, a Huh-7 lunet hepatoma cell line was transiently transfected with an autonomously replicating RNA encoding a bi-cistronic expression construct. This construct comprises a firefly luciferase reporter gene preceding the NS3-NS5B subgenomic region of HCV (genotype 1a H77 or 1b Con1). Translation of the HCV subgenomic region is mediated by an internal ribosome entry site of encephalomyocarditis virus. The construct is furthermore flanked by 5' and 3' untranslated regions of HCV (genotype 1a H77 or 1b Con 1, respectively), which allow for replication of the RNA. In addition to the wild-type constructs, site-directed mutations were introduced into the transient HCV genotype 1b replicon in the gene encoding for the non-structural protein 5A (NS5A). More precisely, amino acid residues 28, 30, 31 and 93 in NS5A were independently altered. Cells were plated in 384 well plates in the presence of test and control compounds, which were added in various concentrations. Following an incubation of two days, replication of the HCV subgenomic replicon RNA was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux™ ultraHTS microplate imager). HCV subgenomic replicon containing cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound was monitored, enabling a dose-response curve for each test compound.
Measurement: EC50 = 0.655 nM (pChEMBL 9.180000305175781)
Descriptors: MW 744.85, ALogP 4.47, HBA 10, HBD 4, PSA 193.1, QED 0.16
Compound (SMILES): CO[C@]12CC[C@@]3(C[C@@H]1COc1ccc(-n4ccnc4)cc1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1C)[C@H]2O5
InChIKey: NILYQWCAXZIPIK-SNYCAXESSA-N
Target: Delta-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41143
Assay: Functional Assay: Functional [35S]GTPgammaS binding assays were conducted as follows. Delta opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 ug/ul delta membrane protein (Perkin Elmer, Shelton, Conn.), 10 ug/mL saponin, 3 uM GDP and 0.20 nM [35S]GTPgammaS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ul/well) was transferred to 96-shallow well polypropylene plates containing 10 ul of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25° C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 ul ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C. for 1-2 hours.
Measurement: EC50 = 75.3 nM (pChEMBL 7.119999885559082)
Descriptors: MW 499.61, ALogP 4.1, HBA 7, HBD 1, PSA 68.98, QED 0.57
Compound (SMILES): COC(=O)c1ccc2c(c1)-c1cccc(c1)[C@@H](N1CCC(c3c(Br)ccc(Cl)c3F)=CC1=O)CCC[C@@H](C)C(=O)N2
InChIKey: BSNSKODJGQKGRG-CLYVBNDRSA-N
Target: Coagulation factor XI (SINGLE PROTEIN), Homo sapiens
UniProt: P03951
Assay: Inhibition Assay: Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). Determinations were made using purified human Factor XIa at a final concentration of 25-200 pM (Haematologic Technologies) and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of 0.0002-0.001 M.
Measurement: Ki > 398 nM (pChEMBL 6.400000095367432)
Descriptors: MW 639.95, ALogP 7.81, HBA 4, HBD 1, PSA 75.71, QED 0.23
Compound (SMILES): CC12C[C@H]3C[C@@H](N4[C@@H]5CCC[C@H]4C[C@@H](n4c(=O)c(N6CC[C@H]6C(=O)O)nc6ccccc64)C5)C[C@@H]1C[C@@H]2C3
InChIKey: YSMGRXHMHZXHMK-PPGQYDOQSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: In Vitro Kappa-Opioid Receptor Functional Assay: Kappa opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 μg/μL kappa membrane protein (in-house), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [35S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μL/well) was transferred to 96-shallow well polypropylene plates containing 10 μL of 20× concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25 °C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 μL ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50 °C. for 2-3 hours. Fifty μL/well scintillation cocktail (MicroScint20, Packard) was added and plates were counted in a Packard Top-Count for 1 min/well.
Measurement: EC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 516.69, ALogP 4.83, HBA 6, HBD 1, PSA 78.67, QED 0.63
Compound (SMILES): COc1ccc2nc(N[C@@H](c3ccc(O)cc3)P(=O)(OC)OC)sc2c1
InChIKey: SMXXEEKTXGMORR-MRXNPFEDSA-N
Target: Amyloid beta-binding alcohol dehydrogenase (SINGLE PROTEIN), Homo sapiens
UniProt: Q2L8D9
Assay: Inhibition Assay: To perform kinetic analyses of the binding of phosphonate derivatives to ABAD, the BIACORE 3000 instrument (based on surface plasmon resonance [SPR] technology) was used.
Measurement: Ki = 14900 nM (pChEMBL 4.829999923706055)
Descriptors: MW 394.39, ALogP 4.61, HBA 8, HBD 2, PSA 89.91, QED 0.57
Compound (SMILES): CO[C@]12CC[C@@]3(C[C@@H]1COCc1ccccc1)[C@H]1Cc4ccc(C(N)=O)c5c4[C@@]3(CCN1C)[C@H]2O5
InChIKey: YWZUTHYBZDSTKA-IPRXQQHWSA-N
Target: Delta-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41143
Assay: Functional Assay: Functional [35S]GTPgammaS binding assays were conducted as follows. Delta opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 ug/ul delta membrane protein (Perkin Elmer, Shelton, Conn.), 10 ug/mL saponin, 3 uM GDP and 0.20 nM [35S]GTPgammaS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ul/well) was transferred to 96-shallow well polypropylene plates containing 10 ul of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25° C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 ul ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C. for 1-2 hours.
Measurement: EC50 = 86 nM (pChEMBL 7.070000171661377)
Descriptors: MW 474.6, ALogP 3.45, HBA 5, HBD 1, PSA 74.02, QED 0.69
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of ERBB2 (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 1081 nM (pChEMBL 5.96999979019165)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Cytoplasmic tyrosine-protein kinase BMX (SINGLE PROTEIN), Homo sapiens
UniProt: P51813
Assay: Inhibition of BMX (unknown origin)
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): CN(c1ccc(S(N)(=O)=O)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
InChIKey: GPWLOCKZXAMXFZ-LLVKDONJSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Enzymatic Assay: JAK1/2/3 kinase assay are performed in vitro using Kit-Tyr 6 Peptide (Invitrogen, Cat. No. PV4122). TYK2 kinase assay are performed in vitro using Z′-LYTE Kinase Assay Kit-Tyr 3 Peptide (Invitrogen, Cat. No. PV3192). Recombinant human JAK1/2/3 or TYK2 catalytic domains are from Invitrogen (Cat No. PV4774/PV4210/PV3855/PV4790); All reactions (20 μL) are started by adding 2.5 μL of the testing compound in 4% DMSO solution, 5 μL of Kinase/Peptide substrate Mixture (3.2, 0.04, 0.2 or 8 μg/mL for Recombinant human JAK1/2/3 catalytic domains, 4 μM for Z-LYTE Tyr 6 peptide or Z-LYTE Tyr 3 peptide) or Phospho-Peptide solution (Invitrogen, Cat. No. PV3192, diluted with 1.33× Kinase Buffer), 2.5 μL ATP Solution (300/100/40/100 μM, JAK1/JAK2/JAK3/TYK2) or 1.33× Kinase Buffer (Invitrogen, Cat. No. PV3189, 5× diluted with distilled water). The 384-well assay plate (Corning, Cat. No. 3575) is mixed and incubated at room temperature for 1 hour. 5 μL of the Development Solution (Dilute Development Reagent A (Cat. No. PV3297) is diluted to 1/64 with Development Buffer (Cat. No. PV3127) for JAK1, JAK2 and JAK3 assay; Development Reagent A (Cat. No. PV3297) is diluted to 1/2048 with Development Buffer (Cat. No. PV3127) for TYK2 assay. The diluted Development Solution is then added to each well, mixed and incubated at room temperature for another 1 hour. The kinase reaction is then stopped by adding 5 μL of the Stop Reagent (Invitrogen, Cat. No. PV3094), and the plate is read with Wallac 1420 VICTOR3 Multilabel Counter (PerkinElmer) at 445 nm and 520 nm fluorescence. All compounds are initially tested at 8 different concentrations (1 μM down to 0.0003 μM) using a 1:3 serial dilution scheme.
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 373.44, ALogP 0.72, HBA 7, HBD 2, PSA 121.1, QED 0.69
Compound (SMILES): COC(=O)c1ccc2c(c1)-c1cccc(c1)[C@@H](N1CCC(c3c(Br)ccc(Cl)c3F)=CC1=O)CCC[C@@H](C)C(=O)N2
InChIKey: BSNSKODJGQKGRG-CLYVBNDRSA-N
Target: Coagulation factor XI (SINGLE PROTEIN), Homo sapiens
UniProt: P03951
Assay: Inhibition Assay: Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). Determinations were made using purified human Factor XIa at a final concentration of 25-200 pM (Haematologic Technologies) and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of 0.0002-0.001 M.
Measurement: Ki > 625 nM (pChEMBL 6.203999996185303)
Descriptors: MW 639.95, ALogP 7.81, HBA 4, HBD 1, PSA 75.71, QED 0.23
Compound (SMILES): COc1ccc2nc(N[C@@H](c3ccc(O)cc3)P(=O)(OC)OC)sc2c1
InChIKey: SMXXEEKTXGMORR-MRXNPFEDSA-N
Target: Amyloid beta-binding alcohol dehydrogenase (SINGLE PROTEIN), Homo sapiens
UniProt: Q2L8D9
Assay: Inhibition Assay: To perform kinetic analyses of the binding of phosphonate derivatives to ABAD, the BIACORE 3000 instrument (based on surface plasmon resonance [SPR] technology) was used.
Measurement: Kd = 291 nM (pChEMBL 6.539999961853027)
Descriptors: MW 394.39, ALogP 4.61, HBA 8, HBD 2, PSA 89.91, QED 0.57
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Receptor tyrosine-protein kinase erbB-4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15303
Assay: Inhibition of ERBB4 (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 22 nM (pChEMBL 7.659999847412109)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Tyrosine-protein kinase CSK (SINGLE PROTEIN), Homo sapiens
UniProt: P41240
Assay: Inhibition of CSK (unknown origin)
Measurement: IC50 = 227 nM (pChEMBL 6.639999866485596)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Tyrosine-protein kinase ITK/TSK (SINGLE PROTEIN), Homo sapiens
UniProt: Q08881
Assay: Inhibition of ITK (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 303 nM (pChEMBL 6.519999980926514)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Receptor tyrosine-protein kinase erbB-4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15303
Assay: Inhibition of ERBB4 (unknown origin)
Measurement: IC50 = 160 nM (pChEMBL 6.800000190734863)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition of JAK3 (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 > 5000 nM (pChEMBL 5.301000118255615)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Tyrosine-protein kinase Fgr (SINGLE PROTEIN), Homo sapiens
UniProt: P09769
Assay: Inhibition of FGR (unknown origin)
Measurement: IC50 = 64 nM (pChEMBL 7.190000057220459)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Tyrosine-protein kinase Tec (SINGLE PROTEIN), Homo sapiens
UniProt: P42680
Assay: Inhibition of TEC (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 1.9 nM (pChEMBL 8.720000267028809)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26
Compound (SMILES): COc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ccc1-c1nc([C@@H]2CC[C@H]3CCC(=O)N3C2)n2ccnc(N)c12
InChIKey: OMIQRSKHABIPRH-AEFFLSMTSA-N
Target: Tyrosine-protein kinase FRK (SINGLE PROTEIN), Homo sapiens
UniProt: P42685
Assay: Inhibition of FRK (unknown origin)
Measurement: IC50 = 154 nM (pChEMBL 6.809999942779541)
Descriptors: MW 565.56, ALogP 4.52, HBA 8, HBD 2, PSA 127.74, QED 0.36
Compound (SMILES): CC(C)(C)/C=C(\C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
InChIKey: KZMQPYCXSAGLTB-ZWUNQBBJSA-N
Target: Tyrosine-protein kinase TXK (SINGLE PROTEIN), Homo sapiens
UniProt: P42681
Assay: Inhibition of RLK (unknown origin) using peptide substrate in presence of ATP by caliper electrophoresis method
Measurement: IC50 = 3.4 nM (pChEMBL 8.470000267028809)
Descriptors: MW 539.62, ALogP 5.67, HBA 8, HBD 1, PSA 122.95, QED 0.26