DOGS Reaction-Driven de novo Design of Bioactive Compounds 英文参考文献.docVIP

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DOGS Reaction-Driven de novo Design of Bioactive Compounds 英文参考文献.doc

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DOGS Reaction-Driven de novo Design of Bioactive Compounds 英文参考文献

DOGS:Reaction-DrivendenovoDesignofBioactive Compounds MarkusHartenfeller1,HeikoZettl1,MiriamWalter2,MatthiasRupp1,FelixReisen1,EwgenijProschak2, SaschaWeggen3,HolgerStark2,GisbertSchneider1* 1Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zu¨rich, Switzerland, 2Goethe- University,InstituteofPharmaceuticalChemistry,LiFF/OSF/ZAFES,FrankfurtamMain,Germany,3DepartmentofNeuropathology,Heinrich-Heine-University,Du¨sseldorf, Germany Abstract We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25’144readily available synthetic building blocks and58 established reaction principles. This enables the softwaretosuggestasynthesisrouteforeachdesignedcompound.Twoprospectivecasestudiesarepresentedtogether with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and c-secretase were synthesized as suggested by the software. The computational approach proved to be suitableforscaffold-hoppingfromknownligandstonovelchemotypes,andforgeneratingbioactivemoleculeswithdrug- likeproperties. Citation:HartenfellerM,ZettlH,WalterM,RuppM,ReisenF,etal.(2012)DOGS:Reaction-DrivendenovoDesignofBioactiveCompounds.PLoSComputBiol8(2): e1002380.doi:10.1371/journal.pcbi.1002380 Editor:JamesM.Briggs,UniversityofHouston,UnitedStatesofAmerica ReceivedOctober24,2011;AcceptedDecember21,2011;PublishedFebruary16,2012 Copyright:?2012