GPCR Library. ChemDiv Inc. 2015

Transcription

1 GPC Library ChemDiv Inc. 2015

2 Knowledge Mining ources 2 PubChem Database Thomson Integrity ciinder ChEMBL Pocketom BindingDB Protein Data Bank MAD cientific publication & Patents ( )

3 Knowledge Progression & election 3 eference Compounds > 80K 2D-Topological analogues privileged hot-spot containing compounds Kohonen-based modeling GPC Library >39.5K 2D-clustering procedure isosteric and bioisosteric morphing singeltones assignment outliers finding and exclusion >15K Templates Design ocus on novel chemistry caffold prioritization MedChem ilters CU VEL CHEMITY GPC-active agents claimed since 2010

4 eference Compounds (Examples) 4 Disclosed since 2010 GP40 agonists Takeda W CC9 eceptor Antagonist ChemoCentryx, Inc. U Muscarinic M1 Agonist Heptares Therapeutics Ltd. U selective inhibitors of the Dopamine D2 receptor + U Department of Health & Human ervices W CGP Antagonist Merck & Co., Inc. U D3 eceptor Ligand AbbVie Inc. U GP119 Agonist Merck & Co., Inc. U GnH (LHH) Antagonist Bayer chering Pharma AG W H eceptor egulator Merck Patent GmbH W D2 eceptor Ligand 5-HT1A eceptor Ligand KACT 2013 U GLP-1 eceptor Ligand Academia inica U CC2 Antagonist Janssen Pharmaceutica V U PL1 Agonist no Pharmaceutical Co., Ltd. W CB2 Agonist Br. Hoffmann-La oche AG W Melanin-Concentrating Hormone MCH eceptor Antagonist H3 eceptor Ligand anofi U mglu regulators BrainCells, Inc. U Takeda Pharmaceutical Co., Ltd W mglu2 Agonist Prostanoid EP4 Antagonist Kaken Pharmaceutical Co., Ltd. W Eli Lilly and Company U CB2 Agonist Boehringer Ingelheim Pharma GmbH & Co. U

5 Methodology for Compound election ef cmpds reported till 2010 ef cmpds reported since 2010 Kohonen-based in silico modeling 5 Holes filling f total: >63K training examples from the clusters (reported GPC ligands) Model 1 1.9K VEL GPC ligands from 2010 ef cmpds reported till 2010 ef cmpds reported since 2010 av. classification power: 77% Descriptors: LogP, p3, PEE_VA_PL, diameter, a_icm, KierA1 f total: 4.3K training examples - singeltones (reported GPC ligands) Model 2 1.9K VEL GPC ligands from 2010 av. classification power: 79%

6 Descriptor Distributions (ref compounds) 6 18 PEE_VA_PL 25 LogP clusters clusters P3 KierA clusters clusters

7 Library Design 120K Compounds selected based on 2D-Topology searching were tested using the developed in silico model Compounds were classified as matched the neurons directly assigned to GPC ligands reported from 2010 Points within the maps indicate the compounds classified as Virtual Hits Model 1 Model 2 7

8 Examples from different areas 8

9 Validation of GPC Library ChemDiv s Design & Activity (PubMed Examples) PA2 Antagonist Compound inhibited the increase in intracellular Ca 2+ levels in trypsin-treated HEK293 cells by 90.5% at 10 g/ml and decreased the production of PGE2 in human synovial W 982 cells by 84% and 119%, respectively, at 0.25 g/ml and 1 g/ml HT6 eceptor Ligand HEK293 human embryonic kidney cells transfected with human receptor Displacement of [3H]-lysergic acid diethylamide K i =19.1 nm PY Y5 Antagonist Hi5 insect cells transfected with human receptor Displacement of [125I]-neuropeptide Y =25 ± 4 nm ulfafurazole Endothelin eceptor Antagonist In TE671 human rhabdomyosarcoma cells transfected with human receptor Displacement of [125I]-endothelin-1 =0.6 µm PA1 Antagonist Displacement of [3H]-thrombin receptor agonist peptide =1.70 µm rexin X-1 Antagonist CH Chinese hamster ovary cells transfected with human X1 receptor luorescent assay <0.3 µm PTGD2 Antagonist Mathiesen, J.M.; et al. 1 ecord(s) etrieved Wo ecord Wo C Wo Identification of indole derivatives exclusively interfering with a G protein-independent signaling pathway of the prostaglandin D2 receptor CTH2 Mol Pharmacol 2005, 68(2): Cannabinoid CB2 Agonist EK293 human embryonic kidney cells transfected with human receptor Displacement of [3H]-WI =5.01 µm GP131 Ligand camp production, induction HEK293 human embryonic kidney cells transfected with human GPBA (TG5) receptor, camp accumulation assay <10 µm Br H H H EP2 eceptor Ligand PK1 Agonist Compound induced PK1 internalization and displayed angiogenic activity in endothelial H5V cells at 1, 10 and 100 nm in a G Matrigel assay. camp production (prostaglandin E2-induced), potentiation C6 rat glioma cells, luorescent assay =0.61 nm P1 Agonist Calcium mobilization, induction eutrophils, human luorescent assay =0.400 ± µm a2-adrenoceptor Antagonist HT29 human colon adenocarcinoma cells K i =0.66±0.06 nm PTGD2 Antagonist W TH Agonist emizol H1 eceptor Antagonist HCV 4B Inhibitor GP109A Agonist Malaria remission/reduction, I VIT Erythrocytes, human, luorescent assay =19 nm camp production, induction HEK293 human embryonic kidney cells transfected with human TH receptor camp accumulation assay =0.660 µm

10 Validation of GPC Library ChemDiv s Design & Activity (PubMed Examples) Prostaglandin D2 receptor Displacement of [3H]PGD2 from human CTH2 receptor expressed in 293 cells by scintillation counting in presence of 0.5% BA =0.064 M G-protein coupled receptor 183 E neuropeptides B/W receptor 1 luorescence-based primary cell-based HT C GPC32 Counter screen for HT for Beta-2A agonists with AP-tagged human GP32 with Powderset3 =0.11 M b2 adrenergic receptor AP method from CP1 = M H hydroxytryptamine receptor 2A Br K MGPX1 Primary cell-based high-throughput screening for identification of compounds that antagonize MrgX1 receptor signaling Luminescence-based cell-based HT =8.393 M peripheral myelin protein chwann cell PMP22 intronic element firefly luciferase assay C glp-1 receptor qht of GLP-1 eceptor Inverse Agonists = M G-protein coupled receptor 183 =22.8 M uht identification of small molecule antagonists of the EBI2 receptor via a luminescent beta-arrestin assay E G-protein coupled receptor 183 uht identification of small molecule antagonists of the EBI2 receptor via a luminescent beta-arrestin assay GPC183 uht identification of small molecule antagonists of the EBI2 receptor via a luminescent beta-arrestin assay guanine nucleotide-binding protein G(i) subunit alpha-1 isoform 1 qht Assay for Inhibitors of G12 GoLoco Motif Activity neuropeptides B/W receptor glp-1 receptor qht of GLP-1 eceptor Inverse Agonists =7.1 M G-protein coupled receptor 55 Image-Based HT =3.3 M C melanin-concentrating hormone receptor 1 neuropeptides B/W receptor 1 E neuropeptides B/W receptor 1 luorescence-based primary cell-based HT melanin-concentrating hormone receptor 1 luorescence-based counterscreen D(2) dopamine receptor isoform (HT Assay) E neuropeptides B/W receptor 1 luorescence-based primary cell-based HT D(1A) dopamine receptor Activ e Antagonist of Human D 1 Dopamine eceptor: qht

11 GPC Library tatistics 11 Diversity in Heterocycles: 700 unique heterocycles usters (Tanimoto metrics, min cmpds per cluster 10, similarity threshold 0.6): 970 ingeltones: 379 Av. structures in cluster: 40 creens: 8691 Diversity: 0.76

12 Examples of caffolds 11

13 Examples of Compounds + Br 12

14 Thank you 14