Identification of Similar Binding Sites to Detect Distant Polypharmacology

Authors

  • Xavier Jalencas,

    1. Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Research Institute & University Pompeu Fabra, Parc de Recerca Biomèdica, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain fax: +34 93 3160550
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  • Jordi Mestres

    Corresponding author
    1. Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Research Institute & University Pompeu Fabra, Parc de Recerca Biomèdica, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain fax: +34 93 3160550
    • Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Research Institute & University Pompeu Fabra, Parc de Recerca Biomèdica, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain fax: +34 93 3160550

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Abstract

The ability of small molecules to interact with multiple proteins is referred to as polypharmacology. This property is often linked to the therapeutic action of drugs but it is known also to be responsible for many of their side effects. Because of its importance, the development of computational methods that can predict drug polypharmacology has become an important line of research that led recently to the identification of many novel targets for known drugs. Nowadays, the majority of these methods are based on measuring the similarity of a query molecule against the hundreds of thousands of molecules for which pharmacological data on thousands of proteins are available in public sources. However, similarity-based methods are inherently biased by the chemical coverage offered by the active molecules present in those public repositories, which limits significantly their capacity to predict interactions with proteins structurally and functionally unrelated to any of the already known targets for drugs. It is in this respect that structure-based methods aiming at identifying similar binding sites may offer an alternative complementary means to ligand-based methods for detecting distant polypharmacology. The different existing approaches to binding site detection, representation, comparison, and fragmentation are reviewed and recent successful applications presented.

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