Journal Article

Prediction of sub-cavity binding preferences using an adaptive physicochemical structure representation

Izhar Wallach and Ryan H. Lilien

in Bioinformatics

Volume 25, issue 12, pages i296-i304
Published in print June 2009 | ISSN: 1367-4803
Published online May 2009 | e-ISSN: 1460-2059 | DOI:

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Motivation: The ability to predict binding profiles for an arbitrary protein can significantly improve the areas of drug discovery, lead optimization and protein function prediction. At present, there are no successful algorithms capable of predicting binding profiles for novel proteins. Existing methods typically rely on manually curated templates or entire active site comparison. Consequently, they perform best when analyzing proteins sharing significant structural similarity with known proteins (i.e. proteins resulting from divergent evolution). These methods fall short when used to characterize the binding profile of a novel active site or one for which a template is not available. In contrast to previous approaches, our method characterizes the binding preferences of sub-cavities within the active site by exploiting a large set of known protein–ligand complexes. The uniqueness of our approach lies not only in the consideration of sub-cavities, but also in the more complete structural representation of these sub-cavities, their parametrization and the method by which they are compared. By only requiring local structural similarity, we are able to leverage previously unused structural information and perform binding inference for proteins that do not share significant structural similarity with known systems.

Results: Our algorithm demonstrates the ability to accurately cluster similar sub-cavities and to predict binding patterns across a diverse set of protein–ligand complexes. When applied to two high-profile drug targets, our algorithm successfully generates a binding profile that is consistent with known inhibitors. The results suggest that our algorithm should be useful in structure-based drug discovery and lead optimization.


Journal Article.  7483 words.  Illustrated.

Subjects: Bioinformatics and Computational Biology

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