J Chem Inf Model - Best of both worlds: on the complementarity of ligand-based and structure-based virtual screening.

Tópicos

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{ detect(2391) sensit(1101) algorithm(908) }

Resumo

Virtual screening with docking is an integral component of drug design, particularly during hit finding phases. While successful prospective studies of virtual screening exist, it remains a significant challenge to identify best practices a priori due to the many factors that influence the final outcome, including targets, data sets, software, metrics, and expert knowledge of the users. This study investigates the extent to which ligand-based methods can be applied to improve structure-based methods. The use of ligand-based methods to modulate the number of hits identified using the protein-ligand complex and also the diversity of these hits from the crystallographic ligand is discussed. In this study, 40 CDK2 ligand complexes were used together with two external data sets containing both actives and inactives from GlaxoSmithKline (GSK) and actives and decoys from the Directory of Useful Decoys (DUD). Results show how ligand-based modeling can be used to select a more appropriate protein conformation for docking, as well as to assess the reliability of the docking experiment. The time gained by reducing the pool of virtual screening candidates via ligand-based similarity can be invested in more accurate docking procedures, as well as in downstream labor-intensive approaches (e.g., visual inspection) maximizing the use of the chemical and biological information available. This provides a framework for molecular modeling scientists that are involved in initiating virtual screening campaigns with practical advice to make best use of the information available to them.

Resumo Limpo

virtual screen dock integr compon drug design particular hit find phase success prospect studi virtual screen exist remain signific challeng identifi best practic priori due mani factor influenc final outcom includ target data set softwar metric expert knowledg user studi investig extent ligandbas method can appli improv structurebas method use ligandbas method modul number hit identifi use proteinligand complex also divers hit crystallograph ligand discuss studi cdk ligand complex use togeth two extern data set contain activ inact glaxosmithklin gsk activ decoy directori use decoy dud result show ligandbas model can use select appropri protein conform dock well assess reliabl dock experi time gain reduc pool virtual screen candid via ligandbas similar can invest accur dock procedur well downstream laborintens approach eg visual inspect maxim use chemic biolog inform avail provid framework molecular model scientist involv initi virtual screen campaign practic advic make best use inform avail

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