Design of Multitarget Activity Landscapes That Capture Hierarchical Activity Cliff Distributions

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• 作者：Dilyana Dimova ; Mathias Wawer ; Anne Mai Wassermann ; Ju虉rgen Bajorath
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：February 28, 2011
• 年：2011
• 卷：51
• 期：2
• 页码：258-266
• 全文大小：1070K
• 年卷期：v.51,no.2(February 28, 2011)
• ISSN：1549-960X

文摘

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鈭抋ctivity 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鈭抋ctivity 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.