J Chem Inf Model - Identification of multitarget activity ridges in high-dimensional bioactivity spaces.

Tópicos

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Resumo

An activity cliff is defined as a pair of structurally similar compounds that have a large difference in potency against a given target. The activity cliff concept has recently been extended in different ways, including the introduction of the activity ridge data structure. An activity ridge consists of two subsets of highly and weakly potent structurally analogous compounds that form all possible pairwise activity cliffs between them. As such, the activity ridge data structure is rich in structure-activity relationship (SAR) information and attractive for SAR analysis. Activity ridges have been detected in various compound data sets. Analogously to single-target activity cliffs, activity rides have thus far only been investigated for individual targets. In this study, we have asked the question whether multitarget activity ridges might also exist. The analysis has been complicated by the limited availability of suitable compound profiling data sets in the public domain. However, in a high-dimensional kinase inhibitor data set recently released by Abbott Laboratories, multitarget activity ridges involving up to 43 different inhibitors and 26 kinase targets were identified. Given the inherently complex architecture of multitarget activity ridges, a new representation format was designed for these ridges based on a scaffold-target matrix. Furthermore, a scoring scheme was developed to identify compounds that were most variably distributed across a multitarget ridge and displayed target differentiation potential. Taken together, our results indicate that multitarget activity ridges represent an attractive data structure for SAR exploration of high-dimensional activity spaces.

Resumo Limpo

activ cliff defin pair structur similar compound larg differ potenc given target activ cliff concept recent extend differ way includ introduct activ ridg data structur activ ridg consist two subset high weak potent structur analog compound form possibl pairwis activ cliff activ ridg data structur rich structureact relationship sar inform attract sar analysi activ ridg detect various compound data set analog singletarget activ cliff activ ride thus far investig individu target studi ask question whether multitarget activ ridg might also exist analysi complic limit avail suitabl compound profil data set public domain howev highdimension kinas inhibitor data set recent releas abbott laboratori multitarget activ ridg involv differ inhibitor kinas target identifi given inher complex architectur multitarget activ ridg new represent format design ridg base scaffoldtarget matrix furthermor score scheme develop identifi compound variabl distribut across multitarget ridg display target differenti potenti taken togeth result indic multitarget activ ridg repres attract data structur sar explor highdimension activ space

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