《药物靶点NATURE综述》

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1、ANALYSISAcomprehensivemapofmoleculardrugtargetsRitaSantos1,2,OlegUrsu3,AnnaGaulton1,A. PatríciaBento1,RameshS. Donadi1,CristianG. Bologa3,AnneliKarlsson1,4,BissanAl-Lazikani5,AnneHersey1,TudorI. Oprea3andJohnP. Overington1,4Abstract

2、Thesuccessofmechanism-based

3、drugdiscoverydependsonthedefinitionofthedrugtarget.Thisdefinitionbecomesevenmoreimportantaswetrytolinkdrugresponsetogeneticvariation,understandstratifiedclinicalefficacyandsafety,rationalizethedifferencesbetweendrugsinthesametherapeuticclassandpredictdrugutili

4、tyinpatientsubgroups.However,drugtargetsareoftenpoorlydefinedintheliterature,bothforlauncheddrugsandforpotentialtherapeuticagentsindiscoveryanddevelopment.Here,wepresentanupdatedcomprehensivemapofmoleculartargetsofapproveddrugs.Wecurateatotalof893humanandpatho

5、gen-derivedbiomoleculesthroughwhich1,578USFDA-approveddrugsact.Thesebiomoleculesinclude667human-genome-derivedproteinstargetedbydrugsforhumandisease.Analysisofthesedrugtargetsindicatesthecontinueddominanceofprivilegedtargetfamiliesacrossdiseaseareas,butalsothe

6、growthofnovelfirst-in-classmechanisms,particularlyinoncology.Weexploretherelationshipsbetweenbioactivityclassandclinicalsuccess,aswellasthepresenceoforthologuesbetweenhumanandanimalmodelsandbetweenpathogenandhumangenomes.Throughthecollaborationofthreeindepende

7、ntteams,wehighlightsomeof1EuropeanMolecularBiologyLaboratory-EuropeantheongoingchallengesinaccuratelydefiningthetargetsofmoleculartherapeuticsandpresentBioinformaticsInstitute(EMBL-conventionsfordeconvolutingthecomplexitiesofmolecularpharmacologyanddrugefficac

8、y.EBI),WellcomeGenomeCampus,Hinxton,CambridgeCB101SD,UK.JamesBlackfamouslystatedin2000that“thebesta‘longtail’ofdiverse,structurallyunrelatedprotein2Presentaddress:waytodiscoveranewdrugistostartwithanoldone”familieswithsmallnumbersofmembers,aswellasComputationa

9、lBiologyandTargetSciences,(REF. 1).Whereavailable,adeepunderstandingofthesingleproteins.GlaxoSmithKlineMedicinesmechanisticactionoftargeteddrugscontinuestoSeveraldatabasesnowprovid