J Chem Inf Model - Design of multitarget activity landscapes that capture hierarchical activity cliff distributions.

Tópicos

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Resumo

An activity landscape model of a compound data set can be rationalized as a graphical representation that integrates molecular similarity and potency relationships. Activity landscape representations of different design are utilized to aid in the analysis of structure-activity relationships and the selection of informative compounds. Activity landscape models reported thus far focus on a single target (i.e., a single biological activity) or at most two targets, giving rise to selectivity landscapes. For compounds active against more than two targets, landscapes representing multitarget activities are difficult to conceptualize and have not yet been reported. Herein, we present a first activity landscape design that integrates compound potency relationships across multiple targets in a formally consistent manner. These multitarget activity landscapes are based on a general activity cliff classification scheme and are visualized in graph representations, where activity cliffs are represented as edges. Furthermore, the contributions of individual compounds to structure-activity relationship discontinuity across multiple targets are monitored. The methodology has been applied to derive multitarget activity landscapes for compound data sets active against different target families. The resulting landscapes identify single-, dual-, and triple-target activity cliffs and reveal the presence of hierarchical cliff distributions. From these multitarget activity landscapes, compounds forming complex activity cliffs can be readily selected.

Resumo Limpo

activ landscap model compound data set can ration graphic represent integr molecular similar potenc relationship activ landscap represent differ design util aid analysi structureact relationship select inform compound activ landscap model report thus far focus singl target ie singl biolog activ two target give rise select landscap compound activ two target landscap repres multitarget activ difficult conceptu yet report herein present first activ landscap design integr compound potenc relationship across multipl target formal consist manner multitarget activ landscap base general activ cliff classif scheme visual graph represent activ cliff repres edg furthermor contribut individu compound structureact relationship discontinu across multipl target monitor methodolog appli deriv multitarget activ landscap compound data set activ differ target famili result landscap identifi singl dual tripletarget activ cliff reveal presenc hierarch cliff distribut multitarget activ landscap compound form complex activ cliff can readili select

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