This article provides an overview of the broad and increasingly varied selection of computational approaches available to find bioisosteric replacements for fragments of bioactive compounds. The rapidly increasing number and diversity of methods has provided medicinal chemists with a powerful range of commercial and academic tools to aid in the optimization of lead compound activity and ADMET properties for drug design. We discuss methods with fundamentally different philosophies, ranging from evaluation of similarity in a calculated property space to cheminformatics analysis of pharmaceutical compound databases. We also discuss the incorporation, within these methods, of a whole spectrum of experimental and calculated data to describe fragment chemistry and compound activity. Despite the growing sophistication of available techniques, there remains much scope for further development and especially for deeper validation of the efficacy of different approaches in what seems set to remain an expanding field.
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Document Type: Research Article
Manchester Interdisciplinary Biocentre (MIB), 131 Princess Street, Manchester M1 7DN and School of Chemistry, Univ. of Manchester, Oxford Road, Manchester M13 9PL, Great Britain.
Publication date: April 1, 2010
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