J Chem Inf Model - Rationalizing the role of SAR tolerance for ligand-based virtual screening.

Tópicos

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Resumo

It is well appreciated that the results of ligand-based virtual screening (LBVS) are much influenced by methodological details, given the generally strong compound class dependence of LBVS methods. It is less well understood to what extent structure-activity relationship (SAR) characteristics might influence the outcome of LBVS. We have assessed the hypothesis that the success of prospective LBVS depends on the SAR tolerance of screening targets, in addition to methodological aspects. In this context, SAR tolerance is rationalized as the ability of a target protein to specifically interact with series of structurally diverse active compounds. In compound data sets, SAR tolerance articulates itself as SAR continuity, i.e., the presence of structurally diverse compounds having similar potency. In order to analyze the role of SAR tolerance for LBVS, activity landscape representations of compounds active against 16 different target proteins were generated for which successful LBVS applications were reported. In all instances, the activity landscapes of known active compounds contained multiple regions of local SAR continuity. When analyzing the location of newly identified LBVS hits and their SAR environments, we found that these hits almost exclusively mapped to regions of distinct local SAR continuity. Taken together, these findings indicate the presence of a close link between SAR tolerance at the target level, SAR continuity at the ligand level, and the probability of LBVS success.

Resumo Limpo

well appreci result ligandbas virtual screen lbvs much influenc methodolog detail given general strong compound class depend lbvs method less well understood extent structureact relationship sar characterist might influenc outcom lbvs assess hypothesi success prospect lbvs depend sar toler screen target addit methodolog aspect context sar toler ration abil target protein specif interact seri structur divers activ compound compound data set sar toler articul sar continu ie presenc structur divers compound similar potenc order analyz role sar toler lbvs activ landscap represent compound activ differ target protein generat success lbvs applic report instanc activ landscap known activ compound contain multipl region local sar continu analyz locat newli identifi lbvs hit sar environ found hit almost exclus map region distinct local sar continu taken togeth find indic presenc close link sar toler target level sar continu ligand level probabl lbvs success

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