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Directed R-Group Combination Graph: A Methodology To Uncover Structure–Activity Relationship Patterns in a Series of Analogues

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Anne Mai Wassermann and Jürgen Bajorath*

Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstrasse 2, D-53113 Bonn, Germany

J. Med. Chem., 2012, 55 (3), pp 1215–1226

DOI: 10.1021/jm201362h

Publication Date (Web): January 16, 2012

*Tel: +49-228-2699-306. Fax: +49-228-2699-341. E-mail: bajorath@bit.uni-bonn.de.

Section:

Pharmacology

Abstract

A graphical method is introduced to study details of structure–activity relationships (SARs) in analogue series that further extends conventional analysis of analogues using R-group tables or related approaches and that provides additional and more differentiated SAR information. The newly designed graph structure represents entire series of analogues in a consistent manner, regardless of their size and complexity of substitution patterns. The approach is specifically tailored toward a systematic exploration and intuitive interpretation of SAR features involving different R-groups and their combinations. Analogues and their potency information are systematically organized on the basis of R-group combinations that are present in a series. This organization scheme results in graph components that represent well-defined SAR patterns. Analysis of these patterns provides an immediate access to critical substitution sites and R-group combinations, favorable and unfavorable R-groups, or nonadditive potency effects of multisite substitutions. Furthermore, the data structure makes it possible to design new analogues by combining favorable R-group combinations derived from different compounds.

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