Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers

Ulrich Zachariae, Fabrizio Giordanetto, Andrew G. Leach

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    Abstract

    The cardiac hERG K channel constitutes a long-standing and expensive antitarget for the drug industry. From a study of the flexibility of hERG around its internal binding cavity, we have developed a new structural model of drug binding to hERG, which involves binding orthogonal to the pore channel and therefore can exploit the up to 4-fold symmetry of the tetrameric channel. This binding site has a base formed by four tyrosine side chains that complement reported ligand-based pharmacophores. The model is able to rationalize reduced hERG potency in matched molecular pair studies and suggests design guidelines to optimize against hERG not relying simply on lipophilicity reduction. The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation.
    Original languageEnglish
    Pages (from-to)4266-4276
    Number of pages11
    JournalJournal of Medicinal Chemistry
    Volume52
    Issue number14
    DOIs
    Publication statusPublished - 23 Jul 2009

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