Binding-Site Assessment by Virtual Fragment Screening 英文参考文献.docVIP

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Binding-Site Assessment by Virtual Fragment Screening 英文参考文献.doc

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Binding-Site Assessment by Virtual Fragment Screening 英文参考文献

Binding-SiteAssessmentbyVirtualFragmentScreening NiuHuang1,2*,MatthewP.Jacobson2 1National Institute of Biological Sciences, Beijing, Beijing, China, 2Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California,UnitedStatesofAmerica Abstract Theaccuratepredictionofproteindruggability(propensitytobindhigh-affinitydrug-likesmallmolecules)wouldgreatly benefitthefieldsofchemicalgenomicsanddrugdiscovery.Wehavedevelopedanovelapproachtoquantitativelyassess proteindruggabilitybycomputationallyscreeningafragment-likecompoundlibrary.InanalogytoNMR-basedfragment screening,wedock,11000fragmentsagainstagivenbindingsiteandcomputeacomputationalhitratebasedonthe fractionofmoleculesthatexceedanempiricallychosenscorecutoff.Weperformalarge-scaleevaluationoftheapproach on four datasets, totaling 152 binding sites. We demonstrate that computed hit rates correlate with hit rates measured experimentally in a previously published NMR-based screening method. Secondly, we show that the in silico fragment screeningmethodcanbeusedtodistinguishknowndruggableandnon-druggabletargets,includingbothenzymesand protein-protein interaction sites. Finally, we explore the sensitivity of the results to different receptor conformations, includingflexibleprotein-proteininteractionsites.Besidesitsoriginalaimtoassessdruggabilityofdifferentproteintargets, this method could be used to identifying druggable conformations of flexible binding site for lead discovery, and suggestingstrategiesforgrowingorjoininginitialfragmenthitstoobtainmorepotentinhibitors. Citation:HuangN,JacobsonMP(2010)Binding-SiteAssessmentbyVirtualFragmentScreening.PLoSONE5(4):e10109.doi:10.1371/journal.pone.0010109 Editor:Jo¨rgLangowski,GermanCancerResearchCenter,Germany ReceivedFebruary8,2010;AcceptedMarch18,2010;PublishedApril9,2010 Copyright:?2010Huang,Jacobson.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermits unrestricteduse,distribution,