薛定谔网络培训 Structure_Based_Virtual_Screening

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1、StructureBasedVirtualScreeningApplicationsandPracticalGuides段践辛SeniorApplicationsScientistApril6th,2010薛定谔DrugDiscoverytoDrugDevelopmentPipelineTargetLeadIDandDevelopmentPhPhPhSelectionOptimizationIIIIII•PreexistingtargetIdentification•Bioavailabilitystud

2、ies–•Efficacy•Literaturetarget•HTSADME•Bioavailability•Genomics•Denovodesign•Long-termtoxicity•Dose•Proteomics•Virtualscreening•Invivoefficacy•SafetyassessmentsOptimization•Synthesisscale-up•Druginteractions•SARstudies•Invivoefficacy•ADMETstudiesTime-cons

3、uming•2-5yrsdiscovery;~13.2yrsdevelopmentCost-intensive•$1.1bn(1995-2000)-$1.7bn(2002-2002)1•TotalR&DcostsforDiscovery2–25%(UK);33%(US)1.Glibert.J.etal.(2003)InVivo,theBusiness&MedicineReport21(10)2.DatafromCMRCompendium,(2002)PhRMASurvey(2002)薛定谔Introduc

4、tion•Virtualscreeningisafastandcosteffectivemethodtogenerateleadsfordrugdesign.•Alternativeorcomplementarytohighthroughputscreening•Virtualscreeningisnotaclick-and-goprocessandrequirescarefulplanning,executionandprocessing•Outlineofthispresentation–Pre-sc

5、reeningconsiderations–Executionofvirtualscreening–Post-screeningprocessing–Applicationexamplesfrompublications薛定谔Pre-ScreeningConsiderations薛定谔QuestionsBeforeVirtualScreening•Whichismytarget?•Ismytargetdruggable?•Whatarethecharacteristicsofmybindingpocket

6、?•Isthetargetstructureflexible?•Whatisthequalityofthetargetstructure?•Whatarethesidechainprotonationstates?Hydrogenbondingnetwork?•DoIhavemultipleconformationsofmytarget?•Water,watereverywhere...薛定谔PreparationofTargetStructure(Proteinpreprationwizard)•Pre

7、paringthePDBstructures•Assigningprotonationstatesandtautomersfortheligand•Hydrogenbondingnetworkoptimization,Asn,Glnflips•Restrainedminimization薛定谔ProtonationStateofSideChains(HIVprotease)薛定谔BindingSiteIdentification,AnalysisandDruggabilityLigandHbondHydr

8、ophobicBIRB796inp38MAPkinaseacceptorregionregionLigandHbonddonorregion薛定谔RunningSiteMap薛定谔QualityofCrystalStructure•Resolution•R-Freevalue•B-factor•Downloadtheelectrondensity•Arethereanyinformationmissing?•Atwhattem