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ID:34858822
大小:1.14 MB
页数:10页
时间:2019-03-12
《Reaction-driven de novo design, synthesis and testing of potential type II kinase inhibitors.pdf》由会员上传分享,免费在线阅读,更多相关内容在学术论文-天天文库。
1、PreliminaryCommuniCationSPeCialFoCuS:ComPutationalChemiStryForreprintorders,pleasecontactreprints@future-science.comReaction-drivendenovodesign,synthesisandtestingofpotentialtypeIIkinaseinhibitorsBackground:Denovodesignofdrug-likecompoundswithadesiredpharmacologicalactivityprofilehasbec
2、omefeasiblethroughinnovativecomputeralgorithms.Fragment-baseddesignandsimulatedchemicalreactionsallowfortherapidgenerationofcandidatecompoundsasblueprintsfororganicsynthesis.Methods:Weusedacombinationofcomplementaryvirtual-screeningtoolsfortheanalysisofdenovodesignedcompoundsthatweregen
3、eratedwiththeaimtoinhibitinactivepolo-likekinase1(Plk1),atargetforthedevelopmentofcancertherapeutics.AhomologymodeloftheinactivestateofPlk1wasconstructedandthenucleotidebindingpocketconformationsintheDFG-inandDFG-outstatewerecompared.Thedenovo-designedcompoundswereanalyzedusingpharmacop
4、horematching,structure–activitylandscapeanalysis,andautomatedliganddocking.Onecompoundwassynthesizedandtestedinvitro.Results:Themajorityofthedesignedcompoundspossessagenericarchitecturepresentinknownkinaseinhibitors.Predictionsfavorkinasesastargetsofthesecompoundsbutalsosuggestpotential
5、off-targeteffects.Severalbioisostericreplacementsweresuggested,anddenovodesignedcompoundswereassessedbyautomateddockingforpotentialbindingpreferencetowardtheinactive(typeIIinhibitors)overtheactiveconformation(typeIinhibitors)ofthekinaseATPbindingsite.Oneselectedcompoundwassuccessfullysy
6、nthesizedassuggestedbythesoftware.Thedenovo-designedcompoundexhibitedinhibitoryactivityagainstinactivePlk1invitro,butdidnotshowsignificantinhibitionofactivePlk1and38otherkinasestested.Conclusions:Computer-baseddenovodesignofscreeningcandidatesincombinationwithligand-andreceptor-basedvir
7、tualscreeninggeneratesmotivatedsuggestionsforfocusedlibrarydesigninhitandleaddiscovery.Attractive,syntheticallyaccessiblecompoundscanbeobtainedtogetherwithpredictedon-andoff-targetprofilesanddesiredactivities.Computationalde novodesignofcandidateinhibitors).Anadditionalhydropho
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