lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): N=C(N)NCCC[C@@H]1NC(=O)c2ccc(cc2)-c2cccc3c(c[nH]c23)C[C@H](C(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O
InChIKey: AOYMGAOYZZQSSW-XJYHXZFBSA-N
Target: Integrin alpha-IIb/beta-3 (PROTEIN COMPLEX), Homo sapiens
UniProt: P05106
Assay: Inhibition of human fibronectin binding to human Integrin alpha2b beta3 receptor incubated for 1 hr by ELISA
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 780.84, ALogP -0.47, HBA 8, HBD 11, PSA 303.58, QED 0.04
Compound (SMILES): CC(C)[C@@H]1NC(=O)[C@]2(C)CSC(=N2)c2csc(n2)CNC(=O)C[C@@H](/C=C/C(F)(F)CS)OC1=O
InChIKey: PDJURBSVOZANDU-STRUHDSTSA-N
Target: Histone deacetylase 3/Nuclear receptor corepressor 2 (HDAC3/NCoR2) (PROTEIN COMPLEX), Homo sapiens
UniProt: O15379
Assay: Inhibition of human recombinant full length C-terminal His-tagged HDAC3 (1 to 428 residues)/N-terminal GST-tagged NCOR2 (395 to 489 residues) expressed in baculovirus infected Sf9 cells using Ac-peptide-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by fluorescence based assay
Measurement: IC50 = 8.21 nM (pChEMBL 8.09000015258789)
Descriptors: MW 532.66, ALogP 2.59, HBA 9, HBD 3, PSA 109.75, QED 0.31
Compound (SMILES): O=C(CCCCCCn1cc(-c2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)nn1)NO
InChIKey: ODMBSJLKYGMCQA-UHFFFAOYSA-N
Target: Histone deacetylase 3/Nuclear receptor corepressor 2 (HDAC3/NCoR2) (PROTEIN COMPLEX), Homo sapiens
UniProt: O15379
Assay: Inhibition of human recombinant full length C-terminal His-tagged HDAC3 (1 to 428 residues)/N-terminal GST-tagged NCOR2 (395 to 489 residues) expressed in insect cells using Boc-l-Lys(Ac)-AMC as substrate preincubated up to 3 hrs and measured after 35 mins by fluorescence assay
Measurement: IC50 = 748 nM (pChEMBL 6.130000114440918)
Descriptors: MW 556.64, ALogP 5.92, HBA 9, HBD 4, PSA 137.57, QED 0.07
Compound (SMILES): Cc1cc(C)n(-c2cccc([C@H](CC(=O)[O-])C[N@@+]3(C)CC[C@@H](CCc4ccc5c(n4)NCCC5)C3)c2)n1
InChIKey: BXOSGYRJKCYDLH-YAYCEGLDSA-N
Target: Integrin alpha-V/beta-3 (PROTEIN COMPLEX), Homo sapiens
UniProt: P05106
Assay: Inhibition of integrin alphavbeta3 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
Measurement: IC50 = 6309.57 nM (pChEMBL 5.199999809265137)
Descriptors: MW 501.68, ALogP 3.57, HBA 6, HBD 1, PSA 82.87, QED 0.45
Compound (SMILES): C=CC(=O)Nc1cccc(Nc2cc(N3CCCC[C@H]3CCO)nc3c(CC)cnn23)c1
InChIKey: CDCHESFKYUNJPV-FQEVSTJZSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P51946
Assay: Competitive irreversible inhibition of CDK7/cyclinH/MAT1 (unknown origin)
Measurement: IC50 = 1200 nM (pChEMBL 5.920000076293945)
Descriptors: MW 434.54, ALogP 3.9, HBA 7, HBD 3, PSA 94.79, QED 0.47
Compound (SMILES): C[C@H](Nc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1)c1ccccc1F
InChIKey: KTUKIQYULOKPOV-JTQLQIEISA-N
Target: SCN2A/SCN1B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q99250
Assay: Inhibition of recombinant human full length Nav1.2 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay
Measurement: IC50 = 47 nM (pChEMBL 7.329999923706055)
Descriptors: MW 413.45, ALogP 4.53, HBA 5, HBD 2, PSA 71.09, QED 0.62
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H](CCCCC(=O)O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@@H]2CSSC[C@H](NC(=O)CN)C(=O)N[C@@H](CSSC[C@@H](C(N)=O)NC1=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N2
InChIKey: ZEIJEIXTXYCHRN-LENJMRGZSA-N
Target: Neuronal acetylcholine receptor; alpha4/beta2 (PROTEIN COMPLEX), Rattus norvegicus
UniProt: P12390
Assay: Antagonist activity at rat alpha4beta2 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced response at -70 mV holding potential by two electrode voltage-clamp assay
Measurement: IC50 = 572 nM (pChEMBL 6.239999771118164)
Descriptors: MW 1759.06
Compound (SMILES): N=C(N)NCCC[C@@H]1NC(=O)c2ccc(cc2)-c2cccc3c(c[nH]c23)C[C@H](C(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O
InChIKey: AOYMGAOYZZQSSW-XJYHXZFBSA-N
Target: Integrin alpha-V/beta-3 (PROTEIN COMPLEX), Homo sapiens
UniProt: P05106
Assay: Binding affinity to integrin alphavbeta3 receptor in human WM115 cells assessed as inhibition of cell adhesion to vitronectin after 0.5 hr by fluorescence assay
Measurement: IC50 = 51000 nM (pChEMBL 4.289999961853027)
Descriptors: MW 780.84, ALogP -0.47, HBA 8, HBD 11, PSA 303.58, QED 0.04
Compound (SMILES): O=C(CC(F)(F)F)N1CCN(Cc2ccnc(Nc3nc4ccc(-c5cnn(CC6CC6)c5)cc4[nH]3)c2)CC1
InChIKey: SSMPZXRXMBEUFU-UHFFFAOYSA-N
Target: IKK epsilon/TBK1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q14164
Assay: Inhibition of IKKepsilon/TBK1 in human MDB-MB-231 cells transduced with lentiviral vector expressing human IRF3 assessed as decrease in poly(I:C)-stimulated IRF3 phosphorylation at S385/386 residues preincubated for 1 hr followed by poly(I:C) addition and measured after 1 hr
Measurement: IC50 = 368 nM (pChEMBL 6.429999828338623)
Descriptors: MW 538.58, ALogP 4.57, HBA 7, HBD 2, PSA 94.97, QED 0.34
Compound (SMILES): Cc1cc(C)n(-c2cccc([C@H](CC(=O)[O-])C[N@@+]3(C)CC[C@@H](CCc4ccc5c(n4)NCCC5)C3)c2)n1
InChIKey: BXOSGYRJKCYDLH-YAYCEGLDSA-N
Target: Integrin alpha-V/beta-5 (PROTEIN COMPLEX), Homo sapiens
UniProt: P06756
Assay: Inhibition of integrin alphavbeta5 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to human vitronectin incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
Measurement: IC50 = 501.19 nM (pChEMBL 6.300000190734863)
Descriptors: MW 501.68, ALogP 3.57, HBA 6, HBD 1, PSA 82.87, QED 0.45
Compound (SMILES): C=CC(=O)Nc1cccc(Nc2cc(N3CCCC[C@H]3CCO)nc3c(CC)cnn23)c1
InChIKey: CDCHESFKYUNJPV-FQEVSTJZSA-N
Target: CDK12/Cyclin K (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9NYV4
Assay: Inhibition of CDK12/Cyclin K (unknown origin) preincubated for 10 mins followed by substrate and ATP addition measured after 200 mins by ADP-Glo luminescence assay
Measurement: IC50 = 74.39 nM (pChEMBL 7.130000114440918)
Descriptors: MW 434.54, ALogP 3.9, HBA 7, HBD 3, PSA 94.79, QED 0.47
Compound (SMILES): COc1nc(-c2nc(Nc3cc(F)cc(C(F)(F)F)c3)n(C)n2)ccc1-n1cnc(C)c1
InChIKey: IEXICYSIZWDQOD-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9NZ42
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 447.4, ALogP 4.28, HBA 8, HBD 1, PSA 82.68, QED 0.46
Compound (SMILES): C[C@H](Nc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1)c1ccccc1F
InChIKey: KTUKIQYULOKPOV-JTQLQIEISA-N
Target: SCN9A/SCN1B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15858
Assay: Inhibition of recombinant human full length Nav1.7 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -60 mV holding potential by whole cell patch clamp assay
Measurement: IC50 = 510 nM (pChEMBL 6.289999961853027)
Descriptors: MW 413.45, ALogP 4.53, HBA 5, HBD 2, PSA 71.09, QED 0.62
Compound (SMILES): O=C(CC(F)(F)F)N1CCN(Cc2ccnc(Nc3nc4ccc(-c5cnn(CC6CC6)c5)cc4[nH]3)c2)CC1
InChIKey: SSMPZXRXMBEUFU-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: Inhibition of recombinant full length human His-tagged CDK9/CyclinT1 expressed in baculovirus expression system using biotin-labelled Ttds-YISPLKSPYKISEG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 25 mins presence of 10 uM of ATP by TR-FRET assay
Measurement: IC50 = 9190 nM (pChEMBL 5.039999961853027)
Descriptors: MW 538.58, ALogP 4.57, HBA 7, HBD 2, PSA 94.97, QED 0.34
Compound (SMILES): Cc1cc(C)n(-c2cccc([C@H](CC(=O)[O-])C[N@@+]3(C)CC[C@@H](CCc4ccc5c(n4)NCCC5)C3)c2)n1
InChIKey: BXOSGYRJKCYDLH-YAYCEGLDSA-N
Target: Integrin alpha-V/beta-8 (PROTEIN COMPLEX), Homo sapiens
UniProt: P06756
Assay: Inhibition of integrin alphavbeta8 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
Measurement: IC50 = 79.43 nM (pChEMBL 7.099999904632568)
Descriptors: MW 501.68, ALogP 3.57, HBA 6, HBD 1, PSA 82.87, QED 0.45
Compound (SMILES): C=CC(=O)Nc1cccc(Nc2cc(N3CCCC[C@H]3CCO)nc3c(CC)cnn23)c1
InChIKey: CDCHESFKYUNJPV-FQEVSTJZSA-N
Target: Cyclin-dependent kinase 13/Cyclin-K (PROTEIN COMPLEX), Homo sapiens
UniProt: Q14004
Assay: Inhibition of CDK13/Cyclin K (unknown origin) preincubated for 10 mins followed by substrate and ATP addition measured after 200 mins by ADP-Glo luminescence assay
Measurement: IC50 = 29.28 nM (pChEMBL 7.53000020980835)
Descriptors: MW 434.54, ALogP 3.9, HBA 7, HBD 3, PSA 94.79, QED 0.47
Compound (SMILES): Cc1cc(C)n(-c2cccc([C@H](CC(=O)[O-])C[N@@+]3(C)CC[C@@H](CCc4ccc5c(n4)NCCC5)C3)c2)n1
InChIKey: BXOSGYRJKCYDLH-YAYCEGLDSA-N
Target: Integrin alpha-V/beta-6 (PROTEIN COMPLEX), Homo sapiens
UniProt: P18564
Assay: Inhibition of integrin alphavbeta6 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
Measurement: IC50 = 3.162 nM (pChEMBL 8.5)
Descriptors: MW 501.68, ALogP 3.57, HBA 6, HBD 1, PSA 82.87, QED 0.45
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(I)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: ADQFBAMWKUTCQJ-UHFFFAOYSA-N
Target: EML4-ALK (CHIMERIC PROTEIN), Homo sapiens
UniProt: Q9HC35
Assay: Inhibition of EML4/ALK (unknown origin) transfected in mouse BAF3 cells assessed as reduction in cell viability after 72 hrs by MTS assay
Measurement: EC50 = 21 nM (pChEMBL 7.679999828338623)
Descriptors: MW 694.6, ALogP 3.95, HBA 10, HBD 3, PSA 132.03, QED 0.18
Compound (SMILES): Br.N#Cc1ccccc1-c1ccc(CN2C3=NCCCN3c3ccccc32)cc1
InChIKey: XPQFQYWKEKXYTE-UHFFFAOYSA-N
Target: AMP-activated protein kinase (AMPK) alpha-1/beta-1/gamma-1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9Y478
Assay: Activation of C-terminal His tagged human recombinant full length AMPK alpha1/beta1/gamma1 expressed in baculovirus infected Sf9 cells using SAMS peptide as substrate incubated for 60 mins by ADP-Glo luminescence assay
Measurement: EC50 = 340 nM (pChEMBL 6.46999979019165)
Descriptors: MW 364.45, ALogP 4.81, HBA 4, HBD 0, PSA 42.63, QED 0.67
Compound (SMILES): C=CC(=O)Nc1ccc(C(=O)Nc2ccc(Nc3n[nH]c4c3CN(C(=O)N[C@H](CN(C)C)c3ccccc3)C4(C)C)cc2)cc1
InChIKey: AVLOXJCCPGBYDS-MUUNZHRXSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50613
Assay: Inhibition of Kinase Activity: Compounds of the invention were assayed for activity against a variety of different kinases.
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 606.73, ALogP 5.59, HBA 6, HBD 5, PSA 134.49, QED 0.15
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCC4)CCCC5)n3)cc2F)cn1
InChIKey: BFZOWFDWBMRNCP-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q92542
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 112 nM (pChEMBL 6.949999809265137)
Descriptors: MW 448.57, ALogP 5.99, HBA 7, HBD 1, PSA 60.56, QED 0.41
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCCC4)CCCC5)n3)cc2F)cn1
InChIKey: GLZJFIVMHISUSH-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q92542
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 225 nM (pChEMBL 6.650000095367432)
Descriptors: MW 462.6, ALogP 6.38, HBA 7, HBD 1, PSA 60.56, QED 0.37
Compound (SMILES): COc1c(C#N)ccc2[nH]c(-c3cn4c(n3)C(C(C)c3ccc(F)cc3)OCC4)cc12
InChIKey: PZXMKCPRRHWSHY-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q92542
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 219 nM (pChEMBL 6.659999847412109)
Descriptors: MW 416.46, ALogP 4.93, HBA 5, HBD 1, PSA 75.86, QED 0.51
Compound (SMILES): Br.N#Cc1ccccc1-c1ccc(CN2C3=NCCCN3c3ccccc32)cc1
InChIKey: XPQFQYWKEKXYTE-UHFFFAOYSA-N
Target: AMP-activated protein kinase (AMPK) alpha-1/beta-1/gamma-1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9Y478
Assay: Activation of C-terminal His tagged human recombinant full length AMPK alpha1/beta1/gamma1 expressed in baculovirus infected Sf9 cells using SAMS peptide as substrate incubated for 60 mins by ADP-Glo luminescence assay
Measurement: EC50 = 338.84 nM (pChEMBL 6.46999979019165)
Descriptors: MW 364.45, ALogP 4.81, HBA 4, HBD 0, PSA 42.63, QED 0.67
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H](CCCCC(=O)O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@@H]2CSSC[C@H](NC(=O)CN)C(=O)N[C@@H](CSSC[C@@H](C(N)=O)NC1=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N2
InChIKey: ZEIJEIXTXYCHRN-LENJMRGZSA-N
Target: Nicotinic acetylcholine receptor alpha6/alpha3/beta2/beta3 (PROTEIN COMPLEX), Rattus norvegicus
UniProt: P04757
Assay: Antagonist activity at rat alpha6alpha3beta2beta3 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced response at -70 mV holding potential by two electrode voltage-clamp assay
Measurement: IC50 = 58.2 nM (pChEMBL 7.239999771118164)
Descriptors: MW 1759.06
Compound (SMILES): Nc1ncnc2c1ccn2[C@@H]1O[C@@H]2COP(=O)([O-])O[C@H]2[C@H]1O.[Na+]
InChIKey: CPVKEMPANUKIKS-DQSPBIHISA-M
Target: CNGA2/CNGA4/CNGB1 (PROTEIN COMPLEX), Rattus norvegicus
UniProt: Q00195
Assay: Activation of recombinant rat CNGA2/CNGA4/CNGB1b heterotetramer expressed in Xenopus laevis oocyte assessed as increase in current amplitude by patch-clamp electrophysiology method
Measurement: EC50 = 360 nM (pChEMBL 6.440000057220459)
Descriptors: MW 328.22, ALogP -0.21, HBA 9, HBD 3, PSA 141.95, QED 0.61
Compound (SMILES): C=CC(=O)Nc1cccc(Nc2cc(N3CCCC[C@H]3CCO)nc3c(CC)cnn23)c1
InChIKey: CDCHESFKYUNJPV-FQEVSTJZSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50613
Assay: Competitive irreversible inhibition of CDK7/cyclinH/MAT1 (unknown origin)
Measurement: IC50 = 1200 nM (pChEMBL 5.920000076293945)
Descriptors: MW 434.54, ALogP 3.9, HBA 7, HBD 3, PSA 94.79, QED 0.47
Compound (SMILES): COc1nc(-c2nc(Nc3cc(F)cc(C(F)(F)F)c3)n(C)n2)ccc1-n1cnc(C)c1
InChIKey: IEXICYSIZWDQOD-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q92542
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 447.4, ALogP 4.28, HBA 8, HBD 1, PSA 82.68, QED 0.46
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCC4)CCCC5)n3)cc2F)cn1
InChIKey: BFZOWFDWBMRNCP-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q96BI3
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 112 nM (pChEMBL 6.949999809265137)
Descriptors: MW 448.57, ALogP 5.99, HBA 7, HBD 1, PSA 60.56, QED 0.41
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCCC4)CCCC5)n3)cc2F)cn1
InChIKey: GLZJFIVMHISUSH-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q96BI3
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 225 nM (pChEMBL 6.650000095367432)
Descriptors: MW 462.6, ALogP 6.38, HBA 7, HBD 1, PSA 60.56, QED 0.37
Compound (SMILES): COc1c(C#N)ccc2[nH]c(-c3cn4c(n3)C(C(C)c3ccc(F)cc3)OCC4)cc12
InChIKey: PZXMKCPRRHWSHY-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q96BI3
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 219 nM (pChEMBL 6.659999847412109)
Descriptors: MW 416.46, ALogP 4.93, HBA 5, HBD 1, PSA 75.86, QED 0.51
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H](CCCCC(=O)O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@@H]2CSSC[C@H](NC(=O)CN)C(=O)N[C@@H](CSSC[C@@H](C(N)=O)NC1=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N2
InChIKey: ZEIJEIXTXYCHRN-LENJMRGZSA-N
Target: Nicotinic acetylcholine receptor alpha6/alpha3/beta2/beta3 (PROTEIN COMPLEX), Rattus norvegicus
UniProt: P43143
Assay: Antagonist activity at rat alpha6alpha3beta2beta3 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced response at -70 mV holding potential by two electrode voltage-clamp assay
Measurement: IC50 = 58.2 nM (pChEMBL 7.239999771118164)
Descriptors: MW 1759.06
Compound (SMILES): COc1nc(-c2nc(Nc3cc(F)cc(C(F)(F)F)c3)n(C)n2)ccc1-n1cnc(C)c1
InChIKey: IEXICYSIZWDQOD-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q96BI3
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 447.4, ALogP 4.28, HBA 8, HBD 1, PSA 82.68, QED 0.46
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCC4)CCCC5)n3)cc2F)cn1
InChIKey: BFZOWFDWBMRNCP-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: P49768
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 112 nM (pChEMBL 6.949999809265137)
Descriptors: MW 448.57, ALogP 5.99, HBA 7, HBD 1, PSA 60.56, QED 0.41
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCCC4)CCCC5)n3)cc2F)cn1
InChIKey: GLZJFIVMHISUSH-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: P49768
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 225 nM (pChEMBL 6.650000095367432)
Descriptors: MW 462.6, ALogP 6.38, HBA 7, HBD 1, PSA 60.56, QED 0.37
Compound (SMILES): COc1c(C#N)ccc2[nH]c(-c3cn4c(n3)C(C(C)c3ccc(F)cc3)OCC4)cc12
InChIKey: PZXMKCPRRHWSHY-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: P49768
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 219 nM (pChEMBL 6.659999847412109)
Descriptors: MW 416.46, ALogP 4.93, HBA 5, HBD 1, PSA 75.86, QED 0.51
Compound (SMILES): COc1nc(-c2nc(Nc3cc(F)cc(C(F)(F)F)c3)n(C)n2)ccc1-n1cnc(C)c1
InChIKey: IEXICYSIZWDQOD-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: P49768
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 447.4, ALogP 4.28, HBA 8, HBD 1, PSA 82.68, QED 0.46
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCC4)CCCC5)n3)cc2F)cn1
InChIKey: BFZOWFDWBMRNCP-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8WW43
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 112 nM (pChEMBL 6.949999809265137)
Descriptors: MW 448.57, ALogP 5.99, HBA 7, HBD 1, PSA 60.56, QED 0.41
Compound (SMILES): Cc1cn(-c2ccc(-c3csc(Nc4c5c(nn4C4CCCC4)CCCC5)n3)cc2F)cn1
InChIKey: GLZJFIVMHISUSH-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8WW43
Assay: Modulation of gamma-secretase in human SH-SY5Y cells overexpressing wild-type human APP751 assessed as inhibition of Abeta42 level after 24 hrs by ELISA
Measurement: IC50 = 225 nM (pChEMBL 6.650000095367432)
Descriptors: MW 462.6, ALogP 6.38, HBA 7, HBD 1, PSA 60.56, QED 0.37
Compound (SMILES): COc1c(C#N)ccc2[nH]c(-c3cn4c(n3)C(C(C)c3ccc(F)cc3)OCC4)cc12
InChIKey: PZXMKCPRRHWSHY-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8WW43
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 219 nM (pChEMBL 6.659999847412109)
Descriptors: MW 416.46, ALogP 4.93, HBA 5, HBD 1, PSA 75.86, QED 0.51
Compound (SMILES): COc1nc(-c2nc(Nc3cc(F)cc(C(F)(F)F)c3)n(C)n2)ccc1-n1cnc(C)c1
InChIKey: IEXICYSIZWDQOD-UHFFFAOYSA-N
Target: Gamma-secretase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8WW43
Assay: Inhibition of gamma secretase in human SKNBE2 cells expressing human APP695 assessed as increase in Abeta38 levels incubated for 18 hrs by sandwich ELISA
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 447.4, ALogP 4.28, HBA 8, HBD 1, PSA 82.68, QED 0.46
Compound (SMILES): COc1cc2c(N)nc(N3CCN(C(=O)C[C@@H](N)c4cccc(Cl)c4)CC3)nc2c(F)c1OC
InChIKey: XNXDHRCGCFBPKW-MRXNPFEDSA-N
Target: Complement factor D (SINGLE PROTEIN), Homo sapiens
UniProt: P00746
Assay: ELISA Assay: CVF-Bb complex prepared from purified cobra venom factor (1 μM), recombinant human complement factor B (expressed in drosophila cells and purified using standard methods) and human complement factor D (expressed in E. Coli, refolded and purified using standard methods). CVF-Bb complex at 3 nM concentration was incubated with test compound at various concentrations for 1 hour at room temperature in PBS pH 7.4 containing 10 mM MgCl2 and 0.05% (w/v) CHAPS. Human complement C3 substrate purified from plasma was added to a final concentration of 1 μM. After 1 hour incubation at room temperature, the enzyme reaction was stopped by addition of a cocktail of concentrated pan-protease inhibitors. The product of the reaction, C3a, was quantified by means of an enzyme-linked-immunosorbent assay.
Measurement: IC50 = 110 nM (pChEMBL 6.960000038146973)
Descriptors: MW 488.95, ALogP 2.76, HBA 8, HBD 2, PSA 119.83, QED 0.54
Compound (SMILES): Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)c(N)s2)c1
InChIKey: ZYRAWKOKVWWJBK-FMKPAKJESA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: PIM Kinase Binding Assay: LC3K assay: PIM-1, -2, and -3 enzymes were generated as fusion proteins expressed in bacteria and purified by IMAC column chromatography (Sun, X., Chiu, J. F., and He, Q. Y. (2005) Expert Rev. Proteomics, 2:649-657). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). Reaction Buffer contained 10 mM HEPES, pH 7.2, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT. Termination Buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35, 0.2% Coating Reagent 3 (Caliper Life Sciences, Hopkinton, Mass.), 20 mM EDTA. Separation Buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35, 0.1% Coating Reagent 3, 1:200 Coating Reagent 8 (Caliper Life Sciences, Hopkinton, Mass.), 10 mM EDTA and 5% DMSO. PIM reactions were carried out in a final volume of 10 μL per well in a 384-well plate. A standard enzymatic reaction, initiated by the addition of 5 μL 2×ATP and test compound to 5 μL of 2× enzyme and FAM-peptide, contained 20 pM PIM1, 50 pM PIM2, or 55 pM PIM3, 1 μM FAM-peptide, and 10 μM ATP, in Reaction Buffer. After 90 minutes of incubation at room temperature, the phosphorylation reaction was stopped by the addition of 10 μL Termination Buffer. The product and substrate in each independent reaction were separated on a 12-sipper microfluidic chip (Caliper Life Sciences, Hopkinton, Mass.) run on a Caliper LC3000® (Caliper Life Sciences, Hopkinton, Mass.). The separation of product and substrate was optimized by choosing voltages and pressure using Caliper's Optimizer software (Hopkinton, Mass.). The separation conditions used a downstream voltage of −500V, an upstream voltage of −2150V, and a screening pressure of −1.2 psi. The product and substrate fluorophore were excited at 488 nm and detected at 530 nm.
Measurement: Ki = 0.024 nM (pChEMBL 10.619999885559082)
Descriptors: MW 462.53, ALogP 3.34, HBA 8, HBD 3, PSA 121.08, QED 0.55
Compound (SMILES): C[C@H](CF)Nc1cc(-n2ccc3cc(C#N)cnc32)ncc1C(=O)NC[C@@H](F)C(C)(C)O
InChIKey: CXTYGPJXWDUYRJ-FZKQIMNGSA-N
Target: Interleukin-1 receptor-associated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NWZ3
Assay: Inhibition Assay: The assays were performed in U-bottom 384-well plates. The final assay volume was 30 L prepared from 15 L additions of enzyme and substrates (fluoresceinated peptide and ATP) and test compounds in assay buffer (20 mM HEPES pH 7.2, 10 mM MgCl2, 0.015% Brij 35 and 4 mM DTT). The reaction was initiated by the combination of IRAK4 with substrates and test compounds. The reaction mixture was incubated at room temperature for 60 min. and terminated by adding 45 μL of 35 mM EDTA to each sample. The reaction mixture was analyzed on the Caliper LABCHIP® 3000 (Caliper, Hopkinton, Mass.) by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data were calculated by comparison to no enzyme control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. The final concentrations of reagents in the assays are ATP, 500 μM; FL-IPTSPITTTYFFFKKK peptide 1.5 μM; IRAK4, 0.6 nM; and DMSO, 1.6%.
Measurement: IC50 = 1.8 nM (pChEMBL 8.739999771118164)
Descriptors: MW 442.47, ALogP 2.9, HBA 7, HBD 3, PSA 115.86, QED 0.49
Compound (SMILES): CN(C)CCOc1ccc([C@H]2COC(=O)N2c2ccc3[nH]cnc3c2)cc1
InChIKey: ULTZAPHRZBZYHB-LJQANCHMSA-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 366.42, ALogP 3.2, HBA 5, HBD 1, PSA 70.69, QED 0.73
Compound (SMILES): CC(C)(C)OC(=O)N1CC[C@@](CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)[C@H](F)C1
InChIKey: LBBZLXMPUULIGG-VGOFRKELSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: HTRF Biochemical Assay: The reactions employed a common peptide substrate, LCB-EQEDEPEGDYFEWLW-NH2 (in-house). The basic assay protocol is as follows: First, 250 nL of diluted compounds in DMSO were dispensed into the wells of a dry 384-well Black plate (Greiner #781076) using a Labcyte Echo 555 acoustic dispenser. Subsequent reagent additions employed an Agilent Bravo. Next, 18 uL of 1.11x enzyme and 1.11x substrate in 1x assay buffer (Invitrogen kinase buffer # PV3189, 2 mM DTT, 0.05% BSA) were added to the wells and shaken and then preincubated for 30 minutes at room temperature to allow compound binding to equilibrate. After equilibration, 2 uL of 10xATP in 1x assay buffer was added to initiate the kinase reaction and the plates were shaken and then incubated at room temperature for 120 minutes. At the end of the incubation, 20 uL of 2x stop buffer (streptavidin-Dylight 650 (Thermo #84547B/100 mL), Eu-tagged pY20 antibody (Perkin Elmer #AD0067), EDTA, HEPES, and Triton) was added to quench the reaction.
Measurement: IC50 = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 460.49, ALogP 3.45, HBA 7, HBD 2, PSA 126.27, QED 0.7
Compound (SMILES): CC(C)[C@@H](NC(=O)c1cc(C(=O)N2CCCC2)c2n1CCOC2)c1ccc(F)cc1
InChIKey: QBDCBSCQTCMGCN-OAQYLSRUSA-N
Target: Potassium channel subfamily K member 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O14649
Assay: TASK-1 Inhibiition Assay: Human TASK-1 channels were expressed in Xenopus oocytes. For this purpose, oocytes were isolated from Xenopus laevis and defoliculated. Subsequently, TASK-1-encoding RNA synthesized in vitro was injected into the oocytes. After two days of TASK-1 protein expression, TASK-1 currents were measured by two-microelectrode voltage clamp. Data were acquired and analyzed using a TEC-10cx amplifier (NPI Electronic, Tamm, Germany) connected to an ITC-16 interface (Instrutech Corp., Long Island, USA) and Pulse software (HEKA Elektronik, Lambrecht, Germany). Oocytes were clamped to -90 mV and TASK-1 mediated currents were measured during 500 ms voltage pulses to 40 mV. Oocytes were continuously superfused with ND96 buffer containing 96 mM sodium chloride, 2 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 5 mM 4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid (HEPES; pH adjusted to 7.4 with sodium hydroxide). All experiments were performed at room temperature.
Measurement: IC50 = 270 nM (pChEMBL 6.570000171661377)
Descriptors: MW 413.49, ALogP 3.52, HBA 4, HBD 1, PSA 63.57, QED 0.82
Compound (SMILES): Cc1cc(-c2nc(-c3ccc(OC(F)F)c(F)c3)n3c2CCO[C@H](C)C3)cc(C)n1
InChIKey: WBKFWXAWWIWBIB-CQSZACIVSA-N
Target: Metabotropic glutamate receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q14416
Assay: [35S]GTPgammaS Binding Assay: The frozen cell membrane fraction prepared as described above was thawed before use, and the resultant was diluted with a buffer for a binding assay (final concentrations: 20 mM HEPES, 100 mM NaCl, 1 mM MgCl2, 3 uM GDP, 300 ug/mL saponin, 0.1% BSA). The compound of each example was added to a cell membrane fraction containing 1.8 to 3 ug/assay of membrane protein on a plate, followed by incubation at room temperature for 30 minutes. Thereafter, with glutamic acid (in a final concentration of 10 uM) added thereto, incubation was performed at room temperature for 15 minutes, and thereafter, [35S]GTPγS (in a final concentration of 0.8 kBq) and 588 ug WGA-SPA beads were added thereto, followed by incubation at room temperature for 1 hour. After the incubation, the plate was subjected to the centrifugal separation at 2,500 rpm and room temperature, and then, membrane cell binding radioactivity was measured with a top count. A [35S]GTPγS binding amount obtained in the presence of glutamic acid was defined as specific binding. On the basis of ratios of inhibiting the specific binding at various concentrations of the compounds of the respective examples, inhibition curves were obtained. Concentrations of the compounds of the respective examples at which the specific [35S]GTPγS binding amount was suppressed by 50% (IC50 values) were calculated on the basis of the inhibition curves.
Measurement: IC50 = 16.1 nM (pChEMBL 7.789999961853027)
Descriptors: MW 417.43, ALogP 4.93, HBA 5, HBD 0, PSA 49.17, QED 0.6
Compound (SMILES): C[C@@H](NC(=O)Nc1cc2[nH]nc(NC(=O)OCC(C)(C)C)c2cn1)c1ccccc1
InChIKey: FBZGYQKHDLCNBR-CYBMUJFWSA-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. The final reaction in each well of 25 uL consists of 0.5 nM hERK2, 900 nM unlabeled peptide, 80 nM labeled-peptide, and 30 uM ATP.
Measurement: IC50 = 355 nM (pChEMBL 6.449999809265137)
Descriptors: MW 410.48, ALogP 4.44, HBA 5, HBD 4, PSA 121.03, QED 0.5
Compound (SMILES): Cc1c(NS(=O)(=O)c2ccc(-c3cccc(C(C)(C)N)c3)cc2)c(CC(C)C)nn1C
InChIKey: PFWXHLNTKMHYOA-UHFFFAOYSA-N
Target: Glycylpeptide N-tetradecanoyltransferase (SINGLE PROTEIN), Trypanosoma brucei brucei (strain 927/4 GUTat10.1)
UniProt: Q388H8
Assay: Enzyme Inhibition Assay: Measurements were performed using a modification of the scintillation proximity assay platform described previously by Georgopapadakou, N. H. et al. (22nd International Congress on Chemotherapy, 2001, Abstract P16.001). Compounds were solubilised in DMSO at a top concentration of 10 mM and serially diluted in half log steps to achieve a range of final assay concentrations of 100 uM to 1 nM. Compound at each concentration (100-fold final) was added to white 384 well plates in a volume of 0.5 ml. Human, A. fumigatus, T. brucei or L. major N-myristoyl transferase enzyme, dissolved to a working concentration of 10 nM in assay buffer (30 mM Tris/HCl pH 7.4, 0.5 mM EGTA, 0.5 mM EDTA, 1.25 mM DTT, 0.1% Triton X-100), was then added to columns 1 to 11 and 13 to 23 of the plates in a volume of 20 ml. To columns 12 and 24, 20 ml assay buffer was added to provide a no enzyme control. Following a 5 minute incubation at room temperature the substrates (GCGGSKVKPQPPQAK(Biotin)-Amide and myristoyl coenzyme A), dissolved in assay buffer, were added to all wells in a volume of 20 ml to start the reaction. The final concentrations of peptide and 3H-myristoyl coenzyme A were 0.5 mM and 125 nM respectively and the specific activity of the radiolabel was 8 Ci/mmol. Plates were then incubated at room temperature for up to 50 minutes (dependant upon the period of linearity for the different enzyme species) before SPA beads, suspended to 1 mg/ml in a stop solution (200 mM Phosphoric Acid/NaOH pH 4, 750 mM MgCl2), were added in a volume of 40 ml.
Measurement: IC50 = 5 nM (pChEMBL 8.300000190734863)
Descriptors: MW 440.61, ALogP 4.59, HBA 5, HBD 2, PSA 90.01, QED 0.56
Compound (SMILES): O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc5ccnn45)[nH]c3n2)C1)N1CCCC1
InChIKey: JORPFOXQSZXEBN-MRXNPFEDSA-N
Target: Diacylglycerol O-acyltransferase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96PD7
Assay: In Vitro DGAT2 Assay: For determination of IC50 values, the reactions were carried out in 384-well white Polyplates (Perkin Elmer) in a total volume of 20 uL. To 1 uL of compounds dissolved in 100% DMSO and spotted at the bottom of each well, 5 uL of 0.04% bovine serum albumin (BSA) (fatty acid free, Sigma Aldrich) was added and the mixture was incubated at room temperature for 20 minutes. To this mixture, 10 uL of hDGAT2 membrane fraction (0.01 mg/mL) diluted in 100 mM Hepes-NaOH, pH 7.4, 20 mM MgCl2 containing 200 nM methyl arachidonyl fluorophosphonate (Cayman Chemical; dried from ethyl acetate stock solution under argon gas and dissolved in DMSO as 5 mM stock) was added. After this mixture was preincubated at room temperature for 2 hours, DGAT2 reactions were initiated by the addition of 4 uL of substrates containing 30 uM [1-14C]decanoyl-CoA (custom-synthesized by Perkin Elmer, 50 mCi/mmol) and 125 uM 1,2-didecanoyl-sn-glycerol (Avanti Polar Lipids) dissolved in 12.5% acetone. The reaction mixtures were incubated at room temperature for 40 min and the reactions were stopped by addition of 5 uL of 1% H3PO4. After the addition of 45 uL MicroScint-E (Perkin-Elmer), plates were sealed with Top Seal-A covers (Perkin-Elmer) and phase partitioning of substrates and products was achieved using a HT-91100 microplate orbital shaker (Big Bear Automation, Santa Clara, Calif.). Plates were centrifuged at 2,000×g for 1 min in an Allegra 6R Centrifuge (Beckman Coulter) and then were sealed again with fresh covers before reading in a 1450 Microbeta Wallac Trilux Scintillation Counter (Perkin Elmer). DGAT2 activity was measured by quantifying the generated product [14C]tridecanoylglycerol in the upper organic phase.
Measurement: IC50 = 54.7 nM (pChEMBL 7.260000228881836)
Descriptors: MW 415.5, ALogP 3.11, HBA 6, HBD 1, PSA 82.42, QED 0.56
Compound (SMILES): COc1cc(-c2nc(-c3ccc(Cl)c(OC)c3)n3c2CCO[C@H](C)C3)cc(C)n1
InChIKey: AXRFPZWPWOAYCB-CQSZACIVSA-N
Target: Metabotropic glutamate receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q14416
Assay: [35S]GTPgammaS Binding Assay: The frozen cell membrane fraction prepared as described above was thawed before use, and the resultant was diluted with a buffer for a binding assay (final concentrations: 20 mM HEPES, 100 mM NaCl, 1 mM MgCl2, 3 uM GDP, 300 ug/mL saponin, 0.1% BSA). The compound of each example was added to a cell membrane fraction containing 1.8 to 3 ug/assay of membrane protein on a plate, followed by incubation at room temperature for 30 minutes. Thereafter, with glutamic acid (in a final concentration of 10 uM) added thereto, incubation was performed at room temperature for 15 minutes, and thereafter, [35S]GTPγS (in a final concentration of 0.8 kBq) and 588 ug WGA-SPA beads were added thereto, followed by incubation at room temperature for 1 hour. After the incubation, the plate was subjected to the centrifugal separation at 2,500 rpm and room temperature, and then, membrane cell binding radioactivity was measured with a top count. A [35S]GTPγS binding amount obtained in the presence of glutamic acid was defined as specific binding. On the basis of ratios of inhibiting the specific binding at various concentrations of the compounds of the respective examples, inhibition curves were obtained. Concentrations of the compounds of the respective examples at which the specific [35S]GTPγS binding amount was suppressed by 50% (IC50 values) were calculated on the basis of the inhibition curves.
Measurement: IC50 = 28.5 nM (pChEMBL 7.539999961853027)
Descriptors: MW 413.91, ALogP 4.55, HBA 6, HBD 0, PSA 58.4, QED 0.63
Compound (SMILES): CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ccc(C#N)nn3)CC2)C[C@@H]1c1ccc(Cl)cc1
InChIKey: DRHKTTLUEWFXLX-SXOMAYOGSA-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 = 23 nM (pChEMBL 7.639999866485596)
Descriptors: MW 577.06, ALogP 4.87, HBA 7, HBD 0, PSA 102.66, QED 0.41
Compound (SMILES): CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)O[C@H](C)CO)c(F)c3)c2C1=O
InChIKey: VWMPKOQTHATNKR-FAEJEUNOSA-N
Target: Serine/threonine-protein kinase mTOR (SINGLE PROTEIN), Homo sapiens
UniProt: P42345
Assay: Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay: The test detects the phosphorylation of the substrate GFP-4EBP1 using a terbium-labelled antibody that is specific for the phospho-Thr46 epitope. Binding of the Tb-antibody to the phosphorylated GFP peptide allows the transfer of energy from Tb, excited at 340 nm, to GFP with an increase in the fluorescence emission of the GFP at 520 nm. The test is performed in 96-well format (Corning/Costar 96 black flat-bottomed half-wells plate, ref. 3694) in a total volume of 30 ul. To 1 ul of inhibitor in 100% DMSO are added (final concentrations) 400 nM of GFP-4EBP1 (Invitrogen PV4759), 8 uM of ATP, 200 ng/ml of enzyme (human recombinant aa mTOR 1360-2549, Invitrogen PV4753) in a buffer of HEPES 50 mM pH 7.5, EGTA 1 mM, MnCl2 10 mM, BSA 0.1 mg/ml, glycerol 0.5%, NV-10 0.1 mg/ml, DTT 2 mM. The mixture is incubated for 30 minutes at room temperature. 10 ul of solution are taken up and the reaction is quenched by adding 10 ul of Tb-antibody solution (Invitrogen PV4757)/EDTA.
Measurement: IC50 = 667 nM (pChEMBL 6.179999828338623)
Descriptors: MW 543.6, ALogP 3.21, HBA 9, HBD 2, PSA 126.35, QED 0.56
Compound (SMILES): Fc1ccc(-c2ncn(-c3ccc([C@H]4CNCCO4)cc3)n2)cc1
InChIKey: XHWKDLRYOUYHFC-QGZVFWFLSA-N
Target: Trace amine-associated receptor 1 (SINGLE PROTEIN), Mus musculus
UniProt: Q923Y8
Assay: Radioligand Binding Assay: HEK-293 cells stably expressing mouse TAAR1 were maintained at 37° C. and 5% CO2 in DMEM high glucose medium, containing fetal calf serum (10%, heat inactivated for 30 min at 56° C.), penicillin/streptomycin (1%), and 375 ug/ml geneticin (Gibco). Cells were released from culture flasks using trypsin/EDTA, harvested, washed twice with ice-cold PBS (without Ca2+ and Mg2+), pelleted at 1,000 rpm for 5 min at 4° C., frozen and stored at -80° C. Frozen pellets were suspended in 20 ml HEPES-NaOH (20 mM, pH 7.4) containing 10 mM EDTA and homogenized with a Polytron (PT 6000, Kinematica) at 14,000 rpm for 20 s. The homogenate was centrifuged at 48,000xg for 30 min at 4° C. Subsequently, the supernatant was removed and discarded, and the pellet resuspended in 20 ml HEPES-NaOH (20 mM, pH 7.4) containing 0.1 mM EDTA using the Polytron (20 s at 14,000 rpm). This procedure was repeated and the final pellet resuspended in HEPES-NaOH containing 0.1 mM EDTA and homogenized.
Measurement: Ki = 3.4 nM (pChEMBL 8.470000267028809)
Descriptors: MW 324.36, ALogP 2.73, HBA 5, HBD 1, PSA 51.97, QED 0.8
Compound (SMILES): CC(C)C[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1ccccc1)C(=O)N[C@H](CNC(=N)N)C(=O)N1CCC(N2CCC[C@H]2C(=O)O)CC1
InChIKey: ACSLJSZFBBPSQA-ROQXEPJXSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Mus musculus
UniProt: P33534
Assay: Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET)-Based cAMP Immunoassay: Mouse R1.G1 cells (ATCC, Manassas, Va.) were grown in suspension in high glucose-DMEM (Dulbecco's Modified Eagle's Medium, Cellgro, Herndon, Va.) containing 10% horse serum and 2% glutaMax (Invitrogen, Carlsbad. Calif.) without added antibiotics. On the day of the experiment, cells were spun at 1,000 rpm for 5 minutes at room temperature and then washed once with HBSS (HEPES Buffered Saline Solution, Invitrogen, Carlsbad, Calif.). Cells were then spun again and resuspended in stimulation buffer (HBSS with 0.05% FAF-BSA (Fatty acid-free bovine serum albumin, Roche Applied Science, Indianapolis, Ind.), 5 mM HEPES) to 2 million cells per ml. Antibody supplied with the LANCE™ cAMP immunoassay kit was then added to the cells according to the manufacturer's instructions, and 12,000 cells per well were then added to the wells containing forskolin to a predetermined fixed final concentration (typically about 2.5 μM) and the previously determined amount of the synthetic peptide amide to be tested. The synthetic peptide amides were tested in a range of concentrations to determine potency. Cells were incubated with the synthetic peptide amide plus forskolin for about 20 minutes at room temperature. After incubation, cells are lysed by adding 12 μl of detection mix as supplied with the LANCE™ kit, followed by incubation for one hour at room temperature. Time resolved fluorescence was read using a 330-380 nm excitation filter, a 665 nm emission filter, dichroic mirror 380, and Z=1 mm.
Measurement: EC50 = 0.349 nM (pChEMBL 9.460000038146973)
Descriptors: MW 733.91, ALogP 0.32, HBA 8, HBD 8, PSA 236.07, QED 0.08
Compound (SMILES): O=c1[nH]c(C2CCN(C3CCOCC3)CC2)nc(N[C@@H]2CCCNC2)c1-c1nc2ccccc2s1
InChIKey: WKOGQAHVFLNYFK-GOSISDBHSA-N
Target: Interleukin-1 receptor-associated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NWZ3
Assay: IMAP technology (Molecular Devices): A 20 ul reaction mixture contains 10 mM TriHCl, pH 7.2, 0.5 nM GST tagged IRAK4 (SignalChem), 100 nM fluorescent peptide substrate (RP7030, Molecular Devices), 100 uM ATP, 1 mM DTT, 1 mM MgCl2, and 0.01% Tween 20. The reaction is initiated by the addition of ATP. After incubation for 30 minutes at 25° C., 60 ul of Progressive IMAP Reagent (Molecular Devices) is added to stop the reaction. Change in RP7030's FP is determined by a FP reader (Analyst HT, LJL BioSystems).
Measurement: IC50 = 440 nM (pChEMBL 6.360000133514404)
Descriptors: MW 494.67, ALogP 3.57, HBA 8, HBD 3, PSA 95.17, QED 0.5
Compound (SMILES): Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(CNc2cccc3ccccc23)cc1
InChIKey: USLQQRGHCAGVTK-UHFFFAOYSA-N
Target: Glycylpeptide N-tetradecanoyltransferase (SINGLE PROTEIN), Trypanosoma brucei brucei (strain 927/4 GUTat10.1)
UniProt: Q388H8
Assay: Enzyme Inhibition Assay: Measurements were performed using a modification of the scintillation proximity assay platform described previously by Georgopapadakou, N. H. et al. (22nd International Congress on Chemotherapy, 2001, Abstract P16.001). Compounds were solubilised in DMSO at a top concentration of 10 mM and serially diluted in half log steps to achieve a range of final assay concentrations of 100 uM to 1 nM. Compound at each concentration (100-fold final) was added to white 384 well plates in a volume of 0.5 ml. Human, A. fumigatus, T. brucei or L. major N-myristoyl transferase enzyme, dissolved to a working concentration of 10 nM in assay buffer (30 mM Tris/HCl pH 7.4, 0.5 mM EGTA, 0.5 mM EDTA, 1.25 mM DTT, 0.1% Triton X-100), was then added to columns 1 to 11 and 13 to 23 of the plates in a volume of 20 ml. To columns 12 and 24, 20 ml assay buffer was added to provide a no enzyme control. Following a 5 minute incubation at room temperature the substrates (GCGGSKVKPQPPQAK(Biotin)-Amide and myristoyl coenzyme A), dissolved in assay buffer, were added to all wells in a volume of 20 ml to start the reaction. The final concentrations of peptide and 3H-myristoyl coenzyme A were 0.5 mM and 125 nM respectively and the specific activity of the radiolabel was 8 Ci/mmol. Plates were then incubated at room temperature for up to 50 minutes (dependant upon the period of linearity for the different enzyme species) before SPA beads, suspended to 1 mg/ml in a stop solution (200 mM Phosphoric Acid/NaOH pH 4, 750 mM MgCl2), were added in a volume of 40 ml.
Measurement: IC50 = 4700 nM (pChEMBL 5.329999923706055)
Descriptors: MW 420.54, ALogP 4.6, HBA 5, HBD 2, PSA 76.02, QED 0.48