lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): Cc1ccc(-c2ccc3ncc4c(c3n2)n(C2CCN(C(=O)CN)CC2)c(=O)n4C)cn1
InChIKey: WOXZNIHCGOBWSW-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 0.32 nM (pChEMBL 9.489999771118164)
Descriptors: MW 431.5, ALogP 1.78, HBA 8, HBD 1, PSA 111.93, QED 0.53
Compound (SMILES): Cc1ccc(-c2ccc3ncc4c(c3n2)n(C2CCN(C(=O)NN)CC2)c(=O)n4C)cn1
InChIKey: VNHKSWWLDVWBFT-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 3.27 nM (pChEMBL 8.479999542236328)
Descriptors: MW 432.49, ALogP 1.87, HBA 8, HBD 2, PSA 123.96, QED 0.28
Compound (SMILES): COc1ncc(-c2ccc3ncc4c(c3n2)n(C2CCN(C)CC2)c(=O)n4C)cn1
InChIKey: MZAXEMDPTLSROA-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 27.5 nM (pChEMBL 7.559999942779541)
Descriptors: MW 405.46, ALogP 2.02, HBA 9, HBD 0, PSA 90.96, QED 0.51
Compound (SMILES): COc1ncc(-c2ccc3ncc4c(c3n2)n(C2CCN(C(=O)CN(C)C)CC2)c(=O)n4C)cn1
InChIKey: UBJPZCYKCVGWGT-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 28.7 nM (pChEMBL 7.539999961853027)
Descriptors: MW 476.54, ALogP 1.47, HBA 10, HBD 0, PSA 111.27, QED 0.43
Compound (SMILES): COc1ncc(-c2ccc3ncc4c(c3n2)n(C2CCN(C(=O)CN)CC2)c(=O)n4C)cn1
InChIKey: KKFNHCJVSBHRAF-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 3.93 nM (pChEMBL 8.40999984741211)
Descriptors: MW 448.49, ALogP 0.87, HBA 10, HBD 1, PSA 134.05, QED 0.49
Compound (SMILES): COc1ncc(-c2ccc3ncc4c(c3n2)n(C2CCN(CCO)CC2)c(=O)n4C)cn1
InChIKey: SLCANOGAKHQGGN-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 11.9 nM (pChEMBL 7.920000076293945)
Descriptors: MW 435.49, ALogP 1.38, HBA 10, HBD 1, PSA 111.19, QED 0.5
Compound (SMILES): COc1ncc(-c2ccc3ncc4c(c3n2)n(C2CCN(C(C)=O)CC2)c(=O)n4C)cn1
InChIKey: FIEGXTNREZBMGI-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 3.87 nM (pChEMBL 8.40999984741211)
Descriptors: MW 433.47, ALogP 1.93, HBA 9, HBD 0, PSA 108.03, QED 0.49
Compound (SMILES): COc1ncc(-c2ccc3ncc4c(c3n2)n(C2CCNCC2)c(=O)n4C)cn1
InChIKey: JECCEISTOFCAKU-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 8.15 nM (pChEMBL 8.09000015258789)
Descriptors: MW 391.44, ALogP 1.67, HBA 9, HBD 1, PSA 99.75, QED 0.57
Compound (SMILES): CN(C)c1ccc(-c2ccc3ncc4c(c3n2)n(C2CCNCC2)c(=O)n4C)cn1
InChIKey: PWFKWGFNTXBANS-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 0.5 nM (pChEMBL 9.300000190734863)
Descriptors: MW 403.49, ALogP 2.34, HBA 8, HBD 1, PSA 80.87, QED 0.57
Compound (SMILES): N[C@H]1CC[C@H](n2c(=O)[nH]c3cnc4ccc(-c5cnc6ccccc6c5)nc4c32)CC1
InChIKey: GGPTUXLMOLCPJR-QAQDUYKDSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 2.21 nM (pChEMBL 8.65999984741211)
Descriptors: MW 410.48, ALogP 3.93, HBA 6, HBD 2, PSA 102.48, QED 0.46
Compound (SMILES): CC(=O)N1CCC(n2c(=O)n(C)c3cnc4ccc(-c5ccc(N(C)C)nc5)nc4c32)CC1
InChIKey: FDWYRWDMLCDEJO-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 0.391 nM (pChEMBL 9.40999984741211)
Descriptors: MW 445.53, ALogP 2.59, HBA 8, HBD 0, PSA 89.15, QED 0.48
Compound (SMILES): CNC(=O)N1CCC(n2c(=O)n(C)c3cnc4ccc(-c5ccc(N(C)C)nc5)nc4c32)CC1
InChIKey: GEFIJVBUAHDDEM-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kalpha using an in vitro kinase assay. PI3-Kalpha activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kalpha reaction resulting in a decrease in FP signal. Mouse PI3-Kalpha P110 and P85 subunits were co-expressed in insect cells and co-purified to homogeneity. PI(4,5)P2 were obtained from Cayman. TAMRA-labeled PI(3,4,5)P3 were from Echelon, Grip1 PH domain from Dundee and other reagents were from Sigma. All assays were performed in a Corning solid black 96-well half area plate using LJL Analyst (Molecular Devices) at room temperature. The assay buffer contained 50 mM HEPES, pH 7.4, 150 mM NaCl.
Measurement: Ki = 0.76 nM (pChEMBL 9.119999885559082)
Descriptors: MW 460.54, ALogP 2.39, HBA 8, HBD 1, PSA 101.18, QED 0.5
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
InChIKey: ZNKKFPUPLGASNG-BHHHAAIVSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate, Ac-DED(Edans)EEAbu-y-[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 uM NS4A cofactor and inhibitor at 30 C. for 10 min.
Measurement: Ki = 1070 nM (pChEMBL 5.96999979019165)
Descriptors: MW 571.63, ALogP 4.57, HBA 7, HBD 2, PSA 127.29, QED 0.43
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCOC(=O)N4C3)nc(Cl)cc2c1
InChIKey: XQNSGMJILVCEJU-RKSFHJAHSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate, Ac-DED(Edans)EEAbu-y-[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 uM NS4A cofactor and inhibitor at 30 C. for 10 min.
Measurement: Ki = 1000 nM (pChEMBL 6)
Descriptors: MW 529.98, ALogP 3.55, HBA 7, HBD 2, PSA 127.29, QED 0.45
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6CC6)C[C@H]5/C=C\CCCCOC(=O)N4C3)nc(Cl)cc2c1
InChIKey: KMRSRQTYTCFVAX-LTYXBVNVSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate, Ac-DED(Edans)EEAbu-y-[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 uM NS4A cofactor and inhibitor at 30 C. for 10 min.
Measurement: Ki = 43 nM (pChEMBL 7.369999885559082)
Descriptors: MW 633.12, ALogP 3.08, HBA 9, HBD 2, PSA 153.23, QED 0.36
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
InChIKey: AWQPGSZGZVXQPF-WKELZURCSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate, Ac-DED(Edans)EEAbu-y-[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 uM NS4A cofactor and inhibitor at 30 C. for 10 min.
Measurement: Ki = 40 nM (pChEMBL 7.400000095367432)
Descriptors: MW 585.66, ALogP 4.96, HBA 7, HBD 2, PSA 127.29, QED 0.4
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCN(C)C(=O)[C@@H]4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
InChIKey: DGROTVCEUFXOSG-DTMGCTNBSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic Assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate,Â  Ac-DED(Edans)EEAbuÃ[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ã¢ Â«ke Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348].
Measurement: Ki = 5 nM (pChEMBL 8.300000190734863)
Descriptors: MW 667.23, ALogP 6.08, HBA 8, HBD 2, PSA 130.95, QED 0.3
Compound (SMILES): COc1cc(-c2ccc(F)c(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
InChIKey: JBGOCYZZJUZJFW-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Nav1.7 In Vitro PX Assay: HEK 293 cells stably transfected with human Nav1.7 were recorded in whole cell voltage clamp mode with the PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, Calif.). Compound effects were measured on a partially inactivated state of the sodium channel. Cells were clamped to a holding potential yielding 20 to 50% inactivation. To elicit sodium current, channels were activated by pulsing to -10 mV for 20 msec. This voltage protocol was repeated at a rate of 0.1 Hz throughout the experiment. A single concentration of test compound was applied to cells for a duration of 3 minutes.
Measurement: IC50 = 15 nM (pChEMBL 7.820000171661377)
Descriptors: MW 527.48, ALogP 4.87, HBA 7, HBD 1, PSA 103.43, QED 0.34
Compound (SMILES): Cl.Cl.Fc1ccc(Nc2nc(NCc3ccncc3)nc(Nc3ccc(F)cc3)n2)cc1
InChIKey: XCZNDDDKPSNOCE-UHFFFAOYSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9ULD8
Assay: Inhibition of BEC1 (unknown origin) expressed in dihydrofolate reductase-deficient CHO cells assessed as decrease in KCl-induced intracellular 86Rb ion release after 20 mins
Measurement: IC50 = 110 nM (pChEMBL 6.960000038146973)
Descriptors: MW 405.41, ALogP 4.64, HBA 7, HBD 3, PSA 87.65, QED 0.41
Compound (SMILES): O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)c(F)c1)Nc1cc(C(F)(F)F)ccc1F
InChIKey: YUEXOEVVUSJCCS-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition Assay: [Experimental method]: Use Lance@Ultra Ulight™-TK assay kit from PerKinElmer to evaluate the inhibitory activity of compounds at KDR kinase. [Instrument]: PerKinElmer's ENVISION plate reader. [Materials]: Optiplate-384 well plate (PerKinElmer), kinase buffer (50 mM Hepes pH7.5, 0.25 mM EGTA, 2 mM DTT, 0.01% Tween 20, 10 mM Mg2+, 0.5 mM Mn2+), KDR kinase (790-1356 AA, Crown Bioscience), KDR kinase substrate (PerKinElmer catalogue # TRF0127-M), Lance@Eu-W1024-anti-phosphotyrosine (PT66) (PerKinElmer, catalogue #AD0068), ATP (Invitrogen), DMSO (Sigma, catalogue #34869), purified water (Millipore, type: Milli-Q). [Study conditions]: Mix KDR (final concentration: 20 nM) and compound (final DMSO: 0.5%), pre-incubate for 20 min at 30° C.; then add ATP (final concentration: 90 μM) and the substrate (final concentration 50 μM). React for 2 hrs at 30° C. After the reaction, add antibody and reaction for 60 min at 30° C. Read the plate (615 nm, 665 nm), calculate the ratio of the value at 665 nm vs 615 nm and analyze the data.
Measurement: IC50 = 8.3 nM (pChEMBL 8.079999923706055)
Descriptors: MW 492.4, ALogP 6.16, HBA 4, HBD 3, PSA 92.35, QED 0.36
Compound (SMILES): CC(C)Oc1ccc(C[C@H]2COC(=O)N2c2ccc3[nH]cnc3c2)cc1
InChIKey: OYOLARFSOLGLBG-INIZCTEOSA-N
Target: Glutaminyl-peptide cyclotransferase (SINGLE PROTEIN), Homo sapiens
UniProt: Q16769
Assay: Spectrophotometic Assay: Spectrophotometic Assay: This novel assay was used to determine the kinetic parameters for most of the QC substrates. QC activity was analyzed spectrophotometrically using a continuous method, that was derived by adapting a previous discontinuous assay (Bateman, R.C.J. 1989 J Neurosci Methods 30, 23-28).
Measurement: IC50 < 10000 nM (pChEMBL 5)
Descriptors: MW 351.41, ALogP 3.92, HBA 4, HBD 1, PSA 67.45, QED 0.76
Compound (SMILES): CC[C@H](C)[C@H](NC(=O)[C@H](CC1CCCCC1)NC(=O)c1cc(CN)no1)C(=O)N1CCC2(C=Cc3ccccc32)CC1
InChIKey: VVIYGZXSHYYCJY-NVLPUFGLSA-N
Target: Proteinase-activated receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P55085
Assay: Antagonist activity at PAR2 in human HT-29 cells assessed as inhibition of 2f-LIGRLO-NH2-stimulated intracellular calcium release preincubated for 30 mins followed by 2f-LIGRLO-NH2 stimulation measured for 60 sec by Fluo-3 AM dye based FLIPR assay
Measurement: IC50 = 8900 nM (pChEMBL 5.050000190734863)
Descriptors: MW 575.75, ALogP 4.32, HBA 6, HBD 3, PSA 130.56, QED 0.39
Compound (SMILES): Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(N3CCCC3)nc12
InChIKey: QWBVDUUFQQRGFB-UHFFFAOYSA-N
Target: Prostaglandin E synthase (SINGLE PROTEIN), Homo sapiens
UniProt: O14684
Assay: Inhibition Assay: mPGES-1 microsome fractions were prepared from CHO-K1 cells transiently transfected with plasmid encoding the human mPGES-1cDNA. Microsomes were diluted with potassium phosphate buffer containing reduced glutathione (pH7.4), and DMSO containing test compound or DMSO alone was added (such that DMSO final concentration would be 1% in each) and incubated at 4° C. for 20 minutes. Then, the enzymatic reactions were initiated by the addition of PGH2 substrate (final concentration 1 μM) and incubated at 4° C. for 60 seconds. The reaction was terminated by the addition of a citrate solution (final citrate concentration 50 mM) containing ferric chloride (final concentration 1 mg/mL). PGE2 production in the enzyme reaction aliquot was measured using HTRF kit (Cisbio International, catalogue #62P2APEC).
Measurement: IC50 = 0.3 nM (pChEMBL 9.520000457763672)
Descriptors: MW 541.96, ALogP 6.65, HBA 4, HBD 3, PSA 90.12, QED 0.26
Compound (SMILES): CN(C)Cc1cccc(N2C(=O)c3ccccc3C2(O)c2ccc3c(c2)NC(=O)CO3)c1
InChIKey: LKIILXJTZLQLGF-UHFFFAOYSA-N
Target: RAF proto-oncogene serine/threonine-protein kinase (SINGLE PROTEIN), Homo sapiens
UniProt: P04049
Assay: Inhibition of c-Raf1 (unknown origin) pre-incubated for 30 mins by luciferase-luciferin-coupled chemiluminescence assay
Measurement: IC50 = 1000 nM (pChEMBL 6)
Descriptors: MW 429.48, ALogP 2.93, HBA 5, HBD 2, PSA 82.11, QED 0.67
Compound (SMILES): C[C@@]1(c2cc(NC(=O)N3CC=C(C#CC4CC4)CC3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
InChIKey: BZKSFWQFKKJRJY-UGKGYDQZSA-N
Target: Beta-secretase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P56817
Assay: In Vitro Enzymatic BACE FRET Assay: The assay buffer used in this screen is 0.05 M acetate, pH 4.2, 10% DMSO final, 100 uM genapol (which is a nonionic detergent, below its Critical Micelle Concentration). The Beta Secretase enzyme (0.2 nM) is pre-incubated for one hour with inhibitors, typically in about 1 uL of DMSO according to a serial dilution, are added thereto. This assay is effectively started by the addition of FRET substrate (50 nM) and the combination is incubated for one hour. The FRET assay is terminated with by addition of Tris buffer, which raises the pH to neutrality, and the fluorescence is determined. The FRET substrate is a peptide with commercially available fluorophore and quencher, on opposite sides of the BACE cleavage site. Proteolytic cleavage of the FRET substrate releases quenching of fluorescence (excitation 488 nm and emission 425 nm).
Measurement: IC50 = 1680 nM (pChEMBL 5.78000020980835)
Descriptors: MW 464.46, ALogP 4.28, HBA 4, HBD 2, PSA 79.95, QED 0.51
Compound (SMILES): Cn1cc(-c2ccncc2)c(-c2ccc(OCc3nc4ccccc4c(=O)n3C)cc2)n1
InChIKey: YWGMJOFUWHMUTC-UHFFFAOYSA-N
Target: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y233
Assay: HTRF Assay: The PDE enzymatic reaction was carried out in assay buffer (20 mM Tris-HCl pH7.5, 10 mM MgCl2, 0.1% bovine serum albumin) containing enzyme and substrate. The PDE enzymes concentration ranged from 10 pM-250 pM, depending on each enzyme's specific activity. The substrate cyclic nucleotide (cAMP or cGMP) concentration used in the assay was 20 nM for PDE10, and 100 nM for other PDEs. The inhibitory effect of compound was determined by incubating various concentration of inhibitor in the enzymatic assay. Typically, compound was serial diluted in DMSO then further diluted in assay buffer. Next, the compound at varying concentration was mixed with PDE enzyme. The reaction was initiated by addition of cyclic nucleotide substrate, and incubated for 60 minutes at 29° C. The reaction was stopped by addition of lysis buffer from assay kit. The cAMP-d2 and anti-cAMP cryptate in the lysis buffer detected the level of cAMP left from the PDE hydrolysis reaction.
Measurement: IC50 = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 423.48, ALogP 3.98, HBA 7, HBD 0, PSA 74.83, QED 0.43
Compound (SMILES): C[C@H](O)[C@@H](NC(=O)Nc1cc2[nH]nc(OCCOC(F)F)c2cn1)c1ccc(F)cc1
InChIKey: VOMIWZNYCCVKGI-MGPLVRAMSA-N
Target: Mitogen-activated protein kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P28482
Assay: IMAP-FP Assay: Activated ERK2 activity was determined in an IMAP-FP assay (Molecular Devices). Using this assay format, the potency (IC50) of each compound was determined from a 10 point (1:3 serial dilution, 3 uM starting compound concentration) titration curve using the following outlined procedure. To each well of a black Corning 384-well plate (Corning Catalog #3575), 7.5 nL of compound (3333 fold dilution in final assay volume of 25 uL) was dispensed, followed by the addition of 15 uL of kinase buffer (tween containing kinase buffer, Molecular Devices) containing 0.0364 ng/mL (0.833 nM) of phosphorylated active hERK2 enzyme. Following a 15 minute compound & enzyme incubation, each reaction was initiated by the addition of 10 uL kinase buffer containing 2.45 uM ERK2 IMAP substrate peptides (2.25 uM-unlabeled IPTTPITTTYFFFK-COOH and 200 nM-labeled IPTTPITTTYFFFK-SFAM (5-carboxyfluorescein)-COOH), and 75 uM ATP.
Measurement: IC50 = 0.4 nM (pChEMBL 9.399999618530273)
Descriptors: MW 439.39, ALogP 2.96, HBA 6, HBD 4, PSA 121.39, QED 0.38
Compound (SMILES): COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4C(=O)Cn3c(OC)cc4cccnc43)cc12
InChIKey: LCMUOUJFKFCCNT-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 9 (SINGLE PROTEIN), Homo sapiens
UniProt: P50750
Assay: LANCE ULight TR-FRET Kinase Assay: CDK9 enzyme activities were measured using LANCE ULight TR-FRET kinase assay reagents (PerkinElmer, Waltham, Mass.). Compounds were directly added in 100% DMSO to white low volume assay plates (Perkin Elmer Proxiplate 6008289) using a Labcyte Echo acoustic dispenser. Assay reagents in serine/threonine kinase assay buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, and 0.0075% Triton X-100. were added for final reaction mixture concentrations of 1000 uM ATP, 100 nM U-light MBP peptide (Perkin Elmer TRF0109M) and reaction initiated with 4 nM CDK9/Cyclin T1 (Carna Biosciences 04-110). The kinase reaction was carried out for 30 minutes before addition of stopping buffer to a final of 20 mM EDTA and 0.5 nM of LANCE Ultra Europium anti-phospho-MBP antibody (PerkinElmer TRF0201M) in LANCE detection buffer (PerkinElmer CR97-100). The reaction was equilibrated for 1 hour and the signal read in the Perkin Elmer Envision in TR-FRET mode.
Measurement: IC50 = 61 nM (pChEMBL 7.210000038146973)
Descriptors: MW 537.6, ALogP 5.58, HBA 6, HBD 1, PSA 85.27, QED 0.31
Compound (SMILES): CC1Cc2ccccc2CN1CC(O)COc1cccc(CNC2CCCC2)c1
InChIKey: UMCYXMWWQWCMFS-UHFFFAOYSA-N
Target: PRMT5/MEP50 complex (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9BQA1
Assay: Inhibition of recombinant human fetal brain FLAG-tagged PRMT5/full length human testis 6His-tagged MEP50 expressed in baculovirus infected insect Sf9 cells using human histone H4 (1 to 15 residues) as substrate preincubated for 30 mins followed by [3H]-SAM addition
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 394.56, ALogP 3.91, HBA 4, HBD 2, PSA 44.73, QED 0.71
Compound (SMILES): CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(N)=O)C(C)C)C(C)C
InChIKey: VQGATQUWRBAAJX-OWWYPNPMSA-N
Target: Tissue factor pathway inhibitor (SINGLE PROTEIN), Homo sapiens
UniProt: P10646
Assay: Binding affinity to TFPI (unknown origin) incubated for 1.5 hrs using tracer peptide JBT0131 by screening ELISA
Measurement: IC50 = 69 nM (pChEMBL 7.159999847412109)
Descriptors: MW 2521.91
Compound (SMILES): CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)c(F)c1
InChIKey: GDTVIWQOTXHFKU-RBJSKKJNSA-N
Target: Neuromedin-K receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P29371
Assay: [3H]SR142801 Competition Binding Assay: hNK3 receptor binding experiment were performed using [3H]SR142801 (Catalog No. TRK1035, specific activity: 74.0 Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane isolated from HEK293 cells transiently expressing recombinant human NK3 receptor. After thawing, the membrane homogenates were centrifuged at 48,000×g for 10 mM at 4° C., the pellets were resuspended in the 50 mM Tris-HCl, 4 mM MnCl2, 1 μM phosphoramidon, 0.1% BSA binding buffer at pH 7.4 to a final assay concentration of 5 μg protein/well. For inhibition experiments, membranes were incubated with [3H]SR142801 at a concentration equal to KD value of radioligand and 10 concentrations of the inhibitory compound (0.0003-10 μM) (in a total reaction volume of 500 μl) for 75 min at room temperature (RT). At the end of the incubation, membranes were filtered onto unitfilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.3% PEI+0.3% BSA, Packard BioScience, Meriden, Conn.) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 μM SB222200 for both radioligands. The radioactivity on the filter was counted (5 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 μl of microscint 40 (Canberra Packard S.A., Zürich, Switzerland) and shaking for 1 h.
Measurement: Ki = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 665.06, ALogP 6.4, HBA 5, HBD 0, PSA 83.05, QED 0.29
Compound (SMILES): COc1cc(CN(Cc2cccnc2)C(C)c2ccc3c(c2)CCO3)ccc1OCCN1C(=O)CCC1=O
InChIKey: MAKAGKNQCLWHAO-UHFFFAOYSA-N
Target: C-X-C chemokine receptor type 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P49682
Assay: Displacement of [125I]-CXCL10 from human recombinant CXCR3 transfected in Flp-In-CHO cell membranes after 60 mins by gamma counting method
Measurement: IC50 = 190 nM (pChEMBL 6.71999979019165)
Descriptors: MW 515.61, ALogP 4.32, HBA 7, HBD 0, PSA 81.2, QED 0.35
Compound (SMILES): Cn1c(Nc2c(Cl)ccc(CNC(=O)[C@@](C)(O)C(F)(F)F)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CCC(C(F)(F)F)CC3)cc21
InChIKey: PJYXYECAJZSWDB-DHPROJGJSA-N
Target: Prostaglandin E synthase (SINGLE PROTEIN), Homo sapiens
UniProt: O14684
Assay: Enzyme Assay: The aim of this assay is to determine the affinity of a test compound for the mPGES-1 enzyme. 47 μl of recombinant human mPGES-1 (0.5 μg protein/well) containing microsomal suspension in a buffer containing GSH, (2.5 mmol/L L-Glutathione reduced, dissolved in 0.1 mol/L Phosphat Buffer pH 7.4) is dispensed in a 384-well plate and thereafter 1 μl of the test compound(s) is/are added and incubated for 25 minutes at room temperature. The enzyme reaction is started by the addition of 2 ul PGH2 (final conc 2 μM) disolved in water-free Diglyme. After 60 seconds the reaction is terminated by addition of a stop solution containing FeCl2 (10 μL 0.074 mol/l FeCl2). The samples are diluted between 1:25 in PBS (Phosphate Buffered Saline). 10 μl of the diluted samples are transferred to 384-well low volume plate.
Measurement: IC50 = 3.9 nM (pChEMBL 8.40999984741211)
Descriptors: MW 805.57, ALogP 8.18, HBA 7, HBD 4, PSA 111.52, QED 0.17
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N3CCC(F)(F)C3)c2n1
InChIKey: GQPOGXLGYYAGLV-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 437.45, ALogP 4.02, HBA 8, HBD 1, PSA 80.99, QED 0.51
Compound (SMILES): C[C@@H](O)[C@H](CO)NC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
InChIKey: JKPWKTNVNHJCOV-ACJLOTCBSA-N
Target: Nicotinamide phosphoribosyltransferase (SINGLE PROTEIN), Homo sapiens
UniProt: P43490
Assay: Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Binding Assay : Probe 2:The assay was carried out in 18 uL low volume plates (Owens Corning) in reaction buffer (50 mM HEPES (NaOH), pH 7.5, 100 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1% Glycerol) using 6.8 nM recombinant, human, C-terminally-His tagged NAMPT, 1 nM Tb-anti-His antibody (Invitrogen, Cat #PV5895), and 200 nM probe (Oregon Green 488-conjugated APO0866; A-1287128.0. Plates were covered, and reactions were carried out for 2-3 hours. Plates were read with Envision (Laser Lantha low volume protocol) after 2 to 3 hours. Excitation was carried out at 337 nm, and the ratio of emission of Oregon Green (520 nm) to terbium (492 nm) was determined and used to calculate IC50 values of test compounds.
Measurement: IC50 = 739 nM (pChEMBL 6.130000114440918)
Descriptors: MW 369.42, ALogP 1.71, HBA 4, HBD 4, PSA 101.9, QED 0.64
Compound (SMILES): COc1cc(OC)cc(N(CCN2CC(C)(C)N=C2C)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: GJSGCDJNBXKAGX-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P22607
Assay: Inhibition of FGFR3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 7244.36 nM (pChEMBL 5.139999866485596)
Descriptors: MW 499.62, ALogP 4.7, HBA 9, HBD 0, PSA 80.9, QED 0.35
Compound (SMILES): Cc1c(Cl)cc(C(F)(F)F)c2nc(CCc3nc(N4CCC(F)(F)C4)nn3C)nn12
InChIKey: UNVGETXXYQFUKG-UHFFFAOYSA-N
Target: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y233
Assay: Scintillation Proximity Assay: The human PDE10A full length assay was performed in 96-well micro titer plates. The reaction mixture of 50 μl contained 20 mM HEPES pH=7.5/10 mM MgCl2/0.05 mg/ml BSA (Sigma cat. # A-7906), 50 nM cGMP (Sigma, cat. # G6129) and 50 nM [3H]-cGMP (GE Healthcare, cat. # TRK392 S.A. 13.2 Ci/mmol), 3.75 ng/well PDE10A enzyme (Enzo Life Science, Lausen, Switzerland cat # SE-534) with or without a specific test compound. A range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50% of the effect (e.g. IC50, the concentration of the competitor inhibiting PDE10A activity by 50%). Non-specific activity was tested without the enzyme. The reaction was initiated by the addition of the substrate solution (cGMP and [3H]-cGMP) and allowed to progress for 20 minutes at room temperature. The reaction was terminated by adding 25 μl of YSi-SPA scintillation beads (GE Healthcare, cat. # RPNQ0150) in 18 mM zinc sulphate solution (stop reagent). After 1 h under shaking, the plate was centrifuged one minute at 170 g to allow beads to settle. Afterwards, radioactive counts were measured on a Perkin Elmer Top-Count Scintillation plate reader.
Measurement: IC50 = 9.78 nM (pChEMBL 8.010000228881836)
Descriptors: MW 449.82, ALogP 3.47, HBA 7, HBD 0, PSA 64.14, QED 0.57
Compound (SMILES): CCc1ncc(Cc2cnc3ccc(N)cc3c2)c2cc(OC)c(OC)cc12
InChIKey: ZWSSLGOTMCGROU-UHFFFAOYSA-N
Target: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y233
Assay: Diaxonhit Phosphodiesterase Assay: The phosphodiesterase assay was developed using the LANCE cAMP kit (PerkinElmer). The assay buffer contained HBSS with 5 mM HEPES, 0.1% BSA, and 1.5 mM MgCl2, pH 7.4. PDE10A (BPS Bioscience) was used at 200 pg/well (with a specific activity of 3200 pmole/min/ug with assay conditions: 10 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 200 uM cAMP, 2.5 kU 5' nucleotidase, 37° C., 20 min) and PDE4D3 (BPS Bioscience) was used at 100 pg/well (with a specific activity of 32713 pmole/min/ug with assay conditions: 10 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 200 uM cAMP, 2.5 kU 5' nucleotidase, 37° C., 20 min). The Biotin-cAMP tracer, supplied in 10 mmol/L Tris-HCl buffered (pH 8.0) salt solution with 1 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1% bovine serum albumin (BSA), and 0.05% sodium azide, is used at a dilution of 1/375. The assay detection mixture contained the LANCE Eu-W8044 labeled streptavidin 1/2250 (supplied in 50 mmol/L Tris-HCl buffer).
Measurement: IC50 = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 373.46, ALogP 4.54, HBA 5, HBD 1, PSA 70.26, QED 0.52
Compound (SMILES): Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(C(C)C)c(=O)c12
InChIKey: NCOOLRRVEOHXRV-ZDUSSCGKSA-N
Target: PI3-kinase p110-delta/p85-alpha (PROTEIN COMPLEX), Homo sapiens
UniProt: O00329
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human p110delta/untagged recombinant full length p85alpha expressed in baculovirus infected Sf21 cells using phosphatidylinositol as substrate in presence of gamma-32P-ATP after 5 mins by thin layer chromatographic method
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 362.44, ALogP 3.73, HBA 6, HBD 2, PSA 88.49, QED 0.58
Compound (SMILES): NC(=O)N1CCCc2cc(-c3cncc(COc4ccc(F)cc4)c3)cnc21
InChIKey: ULUHWNZSWFARDN-UHFFFAOYSA-N
Target: Cytochrome P450 11B2, mitochondrial (SINGLE PROTEIN), Homo sapiens
UniProt: P19099
Assay: Aldosterone Synthase Inhibition Assay: The aldosterone synthase inhibition assay employs cynomolgus adrenal gland mitochondria as the source of aldosterone synthase (CYP11B2). Mitochondria are prepared from frozen cynomolgus monkey adrenal glands according to Method A described in by J. D. McGarry et al. (Biochem. J., 1983, 214, 21-28), with a final resuspension in the AT buffer described in R. Yamaguchi et al. (Cell Death and Differentiation, 2007, 14, 616-624), frozen as aliquots in liquid nitrogen and stored at -80° C. until use. Assays are performed in 96-well format in a final volume of 60 uL/well, containing 100 mM potassium phosphate, pH 7.4, 1% (v/v) DMSO, and additionally, 2 uM of corticosterone and 6 mg of mitochondrial protein. Reactions are started by the addition of NADPH to 1 mM and allowed to proceed for 60-90 minutes at 37° C. Reactions are terminated by the addition of 60 uL of acetonitrile. One hundred microliters are then transferred to a glass filter plate and centrifuged at 570xg.
Measurement: IC50 = 5.4 nM (pChEMBL 8.270000457763672)
Descriptors: MW 378.41, ALogP 3.69, HBA 4, HBD 1, PSA 81.34, QED 0.75
Compound (SMILES): CCc1ccccc1NC(=O)Nc1ccc(Cl)c(S(=O)(=O)C2CCNCC2)c1O
InChIKey: KEIVOVSJTKSMSG-UHFFFAOYSA-N
Target: C-X-C chemokine receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P25024
Assay: Displacement of [125I]IL8 from recombinant human CXCR1 expressed in CHO cell membranes measured after 1 hr by TopCount scintillation counting method
Measurement: IC50 < 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 437.95, ALogP 3.78, HBA 5, HBD 4, PSA 107.53, QED 0.53
Compound (SMILES): CCCCCCCN1C[C@H](CO)[C@@H](O)[C@H](O)C1
InChIKey: FQBCZWBBRFJEFK-JHJVBQTASA-N
Target: Lysosomal acid glucosylceramidase (SINGLE PROTEIN), Homo sapiens
UniProt: P04062
Assay: Enzyme Assay: To 2.5 μl of supernatant (in 96-well plates) was added 17.5 μl reaction buffer (citrate phosphate buffer, pH 4.5, no Triton X-100), and 50 μl of 4-methyl umbelliferone (4-MU)-labeled substrate, β-glucopyranoside, or a labeled negative controls α-glucopyranoside or α-galacatopyranoside). Plates were incubated at 370 for 1 hour, followed by the addition of 70 μl stop buffer (0.4 M glycine-NaOH, pH 10.6). Activity of GCase was determined by measuring the emission at 460 nm by exciting at 355 nm using a 1 second read time per well (Victor2 multilabel counter-Wallac).
Measurement: Ki = 17280 nM (pChEMBL 4.760000228881836)
Descriptors: MW 245.36, ALogP 0.6, HBA 4, HBD 3, PSA 63.93, QED 0.57