Form follows function: Shape analysis of protein cavities for receptor-based drug design

Authors

  • Martin Weisel,

    1. Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Frankfurt am Main, Germany
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  • Ewgenij Proschak,

    1. Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Frankfurt am Main, Germany
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  • Jan M. Kriegl,

    1. Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
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  • Gisbert Schneider Professor

    Corresponding author
    1. Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Frankfurt am Main, Germany
    • Johann Wolfgang Goethe-Universität, Beilstein Endowed Chair for Cheminformatics, Institut für Organische Chemie und Chemische Biologie, Siesmayerstr. 70, D-60323 Frankfurt am Main, Germany Fax: +49-69-798-24880
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Abstract

Identification of potential ligand-binding pockets is an initial step in receptor-based drug design. While many geometric or energy-based binding-site prediction methods characterize the size and shape of protein cavities, few of them offer an estimate of the pocket's ability to bind small drug-like molecules. Here, we present a shape-based technique to examine binding-site druggability from the crystal structure of a given protein target. The method includes the PocketPicker algorithm to determine putative binding-site volumes for ligand-interaction. Pocket shape descriptors were calculated for both known ligand binding sites and empty pockets and were then subjected to self-organizing map clustering. Descriptors were calculated for structures derived from a database of representative drug-protein complexes with experimentally determined binding affinities to characterize the “druggable pocketome”. The new method provides a means for selecting drug targets and potential ligand-binding pockets based on structural considerations and addresses orphan binding sites.

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