ChEMBL US tour December 2014

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Slides from a tour of a number of US labs in December 2014

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<ul><li> 1. ChEMBL:ResourcesforDrugDiscoveryJohnP.Overington@johnpoveringtonjpo@ebi.ac.uk</li></ul> <p> 2. EMBL-EBI 3. ChEMBLStrategy Comprehensivelycataloguehistoricaldrugdiscovery Includesuccessesandfailures LargescaleabstracHoncuraHonofprimaryliterature DirectdeposiHons Drugscanbesmallmolecules,pepHdes,recombinantproteins,siRNA,cells,viruses,etc. Learnrulesfordrugdiscoverysuccess TargetselecHonandprioriHsaHon-druggability Leaddiscovery,opHmisaHon,clinicalcandidateselecHon Developapproachestonewtargetclassese.g.PPIs MakealldatafreelyavailabletoenHrecommunity Encouragere-use,integraHonandcross-linking 4. TargetDiscoveryLeadDiscoveryLeadOpHmisaHonPreclinicalDevelopmentPhase1Phase2Phase3Launch(Phase4)DrugDiscovery&gt;1,638,000compoundrecords&gt;12,800,000bioacHviHes~57,150abstractedpapers~10,579targets~12,000clinicalcandidates~1,600drugsTargetidenHficaHonMicroarrayprofilingTargetvalidaHonAssaydevelopmentBiochemistryClinical/AnimaldiseasemodelsHigh-throughputScreening(HTS)Fragment-basedscreeningFocusedlibraries ScreeningcollecHonMedicinalChemistryStructure-baseddrugdesignSelecHvityscreensADMETscreensCellular/AnimaldiseasemodelsPharmacokineHcsToxicologyInvivosafetypharmacologyFormulaHonDosepredicHonPKtolerabilityEfficacySafety&amp;EfficacyIndicaHondiscovery,repurposing&amp;expansionMed.Chem.SARClinicalCandidatesDrugsDiscoveryDevelopmentUseChEMBLcontentChEMBL19content 5. PrototypeDrug Optimisation1stgeneraHon2ndgeneraHon3rdgeneraHon4thgeneraHonNONOOHNNNCl ClNNNONONOOHNNNCl ClTinidazole 1970NNONOO OOOHNNCl ClNNN+OOAzomycin(1956)Streptomycesnatural producttrichomonacidaltoxicNNN+OOOMetronidazole 1962NNClClotrimazole 1970NNClClOClClMiconazole 1970NNClClOClEconazole 1972Ketoconazole 1978 Itraconazole 1984NNClClSClNN+OOSSulconazole 1980NNBifonazole 1981Terconazole 1980OHPosaconazole 2005FOONNF FN NFFNOHNNNNNNONNVoriconazole 2002NOHNNNNNFFFluconazole 1988NFosfluconazole 2004ImidazoletriazoleONNNNNFFPOOHOHNNNNNAfter W. Sneader 6. OverviewofEMBL-EBIChemistryResourcesRDFandRESTAPIinterfaces40K1.5M&gt;15M15K750UniChemInChI-basedresolver(full+relaxedlenses)3rdPartyDataZINC,PubChem,ThomsonPharmaDOTF,IUPHAR,DrugBank,KEGG,NIHNCC,eMolecules,FDASRS,PharmGKB,Selleck,.ChEMBLBioacHvitydatafromliteratureanddeposiHonsChEBIStructuresandmetadataformetabolites.ChemicalOntologyAtlasLigand-inducedtranscriptresponsePDBeLigandstructuresfromstructurallydefinedproteincomplexesSureChEMBLLigandstructuresfrompatentliteratureRESTAPIInterface~75M 7. ChEMBL 8. WhatIstheChEMBLData? 9. SARDataCompoundAssayKi=4.5nM&gt;ThrombinMAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLERECVEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETGDGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQKVIDQFGEED2=230nMWhatIstheChEMBLData?Inhibition ofhuman ThrombinPTT (partialthromboplastintime) 10. ChEMBLTargetTypesProteinProteincomplexProteinfamilyNucleicAcide.g.NicoHnicacetylcholinereceptore.g.Muscarinicreceptorse.g.DNAe.g.HEK293cellse.g.Tracheae.g.Drosophilae.g.PDE5CelllineTissueSub-cellularfracHonOrganism 11. ChEMBLhqps://www.ebi.ac.uk/chembl Theworldslargestprimarypublicdatabaseofmedicinalchemistrydata ~1.6millioncompounds,~10,000targets,~12millionbioacHviHes TrulyOpenData-CC-BY-SAlicense ChEMBLdataalsoloadedintoBindingDB,PubChemBioAssayandBARDA.Gaultonetal(2012)NucleicAcidsResearchDatabaseIssue.40D1100-1107 12. SureChEMBLhqps://www.surechembl.org NewPublicchemistrypatentresource AcquiredSureChemproductfromDigitalScience AutomaHcallyextractedchemicalstructuresfromfull-textpatent ~15millionchemicalstructures Updateddaily Plantoaddmoleculartarget,sequence,disease,animalmodel,cell-lineindexing. 13. hqps://www.ebi.ac.uk/chembl 14. AboutChEMBL 15. CompoundView-1 16. CompoundView-2 17. CompoundView3 18. CompoundView-4 19. TargetSearch 20. BrowseTargets 21. BrowseTargets-Organism 22. BrowseDrugs 23. Drugs 24. TargetsofLaunchedDrugsOveringtonetal,Nat.Rev.DrugDisc.,5,pp.993-996(2006) 25. DrugTargetsandDrugsSantosetal,unpublished 26. DifferentTypesofDrugsSantosetal,unpublishedSyntheHcsmallmoleculeNaturalproduct-derivedsmallmoleculeMonoclonalanHbodyOtherproteinPolymerPepHdeOligonucleoHdeOligosaccharideInorganicOtherOtherDrugsApproved2013AssignedUSANs2013 27. AffinityofDrugsfortheirTargetsKi,Kd,IC50,EC50,&amp;pA2endpointsfordrugsagainsttheirefficacytargets23456789101112400350300250200150100500Frequency-log10affinity10mM1mM100mM10mM1mM100nM10nM1nM100pM10pM1pMOverington,etal,NatureRev.DrugDiscov.5pp.993-996(2006)Gleesonetal,NatureRev.DrugDiscov.10pp.197-208(2011) 28. PrivilegedTargetFamiliesRhodopsin-likeGPCRPDBe:3sn6IonchannelsPDBe:4kfmNuclearreceptorsPDBe:3e00ProteinkinasesPDBe:4foc22%ofdrugtargets33%ofsmallmoldrugs12%ofdrugtargets18%ofsmallmoldrugs6%ofdrugtargets17%ofsmallmoldrugs13%ofdrugtargets2.4%ofsmallmoldrugsOver53%ofalltargetsand70%ofdrugsmodulatethesefourtargetclasses 29. Santos,unpublishedPrivilegedTargetFamiliesChEMBL17Drugs 30. NFBPathway 31. FDAApprovedDrugs 32. ClinicalCandidates 33. ClinicalCandidates 34. ClinicalCandidates DatabaseofclinicaldevelopmentcandidatesContains~12,0002-Dstructures/sequencesEsHmatedsize~35-45,000compoundsWorkinprogress Deepercoverageofkeygenefamilies e.g.Proteinkinases,399disHnctclinicalcandidates 35. PharmaIndustryProducHvityFileRegistraHonnumbervs.USANdate800,000700,000600,000500,000400,000300,000200,000100,0000Phase 2b date~Discovery date19601965197019751980198519901995200020052010Overington,unpublished 36. ClinicalKinomeOverington,Al-Lazikani&amp;Wennerberg,unpublished 37. KinaseInhibitorsinClinicalDevelopmentOverington,Bellis,Al-Lazikani&amp;Wennerberg,unpublished 38. ClinicalKinome 399Clinicalstagehumansmallmoleculeproteinkinaseinhibitors 29Approvedsmallmoleculekinaseinhibitors 38Phase3 143Phase2 189Phase1 Phase1:2raHoisatypicalduetomanykinaseinhibitortrialsbeingphase1/2oncologytrials 2Dstructuresfor311ofthese 39. KinaseInhibitorPolypharmacologyStaurosporine(notrials)USlaunchedSuniHnibSorafenibImaHnibDasaHnibTofaciHnibTozaserHb(Ph.II)ErloHnibGefiHnibLapaHnibAdaptedfromGhoreschietal,NatureImmunology10,356-360(2009) 40. GSKPKISData 41. ChEMBLAssayReliability 42. F.A. Krger &amp; J.P.Overington (2012)Global analysis of smallmolecule binding torelated protein targetsPLoS Comp. Biol. 8,e1002333 43. Differences Between Human And Rat Orthologs44Distribution of affinity differencesHuman vs RatpKdHumanpKdRat-log(Kd)Humandensity|humanpKd-ratpKd| 44. 45Differences Between Different AssaysDistribution of inter-assay affinity differencesdensityBinding affinity in human and ratassayspKdAssay1pKdAssay2|humanpKd-humanpKd| 45. Ortholog vs Intra-assay DifferencesDensity distributions of ortholog andinter-assay differencespKii-pKijdensityKrger,PLoSComp.Biol.8,e1002333,DOI:10.1371/journal.pcbi.1002333 46. ChEMBLDomainAnnotaHon 47. Domain-levelAnnotaHon Site of binding is important in understanding and controllingfunction often several sites within same target protein Recently annotated binding sites (where possible) for entireChEMBL target dictionary used Pfam domains http://www.pfam.org 48. DomainpoisoningofsequencequeriesKinaseSYK(Q64725),Krger BMC Bioinformatics, 13, S11 DOI:10.1186/1471-2105-13-S17-S11R.norvegicusPhosphataseSH-PTP2(P35235),R.norvegicus 49. Domain-levelBindingSitesDepleted and Enriched Pfam DomainsNeur_chan_memb -1.63zf-C4 -0.94ANF_receptor -0.88SH2 -0.83Pkinase_C -0.70fn3 -0.53SH3_1 -0.51Lig_chan -0.50C2 -0.50C1_1 -0.50Guanylate_cyc -0.46HATPase_c -0.46I-set -0.44adh_short -0.39PH -0.39Ank -0.39..Metallophos 0.35Phospholip_A2_1 0.38Peptidase_M10 0.41Asp 0.45SNF 0.48Hist_deacetyl 0.48Carb_anhydrase 0.50Peptidase_C1 0.51Trypsin 0.51Beta-lactamase 0.57p450 1.00Hormone_recep 1.19Ion_trans 1.66Neur_chan_LBD 2.02Pkinase_Tyr 2.12Pkinase 5.877tm_1 7.30KruegerandOverington,unpublished 50. Binding Between Multiple DomainsIdenHfiedonly12mulH-domainarchitectures(correspondingto120ChEMBLtargets)withligandbindingmediatedviamorethanonedomain.PDBe:3goiKrger BMC Bioinformatics, 13, S11 DOI:10.1186/1471-2105-13-S17-S11 51. hqps://www.ebi.ac.uk/chembl/research/ppdms 52. Better prediction of pathway perturbationOverington, unpublished 53. Domain specific modulation mTorHEAT repeat FAT FRB kinase RD FATCmTORC1DEPTORMLST8 mSIN1RaptorRheb FKBP-38 mSLT8Sirolimus (rapamycin) PI-103rGableRictorTel2 FBXW7DEPTORFKBP-12S6K1Overington, unpublishedPRAS40mTORC2FKBP-12bindingmTORCbindingImmunosuppression, Cancer Cancer 54. AcknowledgementsChEMBLDatabaseAnneHerseyAnnaGaultonMarkDaviesMichalNowotkaGeorgePapadatosJonChambersLouisaBellisRitaSantosGerardVanWestenRuthAkhtarFrancisAtkinsonPatriciaBentoRameshDonadiJohnPaulOveringtonIns5tuteofCancerResearchBissanAl-LazikaniPaulWorkmanFIMM,HelsinkiKristerWennerbergUniversityofDundeeAndrewHopkinshqp://chembl.blogspot.com </p>