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The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand

Authors

  • Dr. Matthew R. Lockett,

    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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    • These authors contributed equally to this work.

  • Dr. Heiko Lange,

    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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    • These authors contributed equally to this work.

  • Dr. Benjamin Breiten,

    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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    • These authors contributed equally to this work.

  • Dr. Annie Heroux,

    1. Photon Sciences Directorate, Building 745, Brookhaven National Laboratory, Upton, NY 11973 (USA)
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  • Dr. Woody Sherman,

    1. Schrödinger Inc., 120 West 45thStreet, New York, NY 10036 (USA)
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  • Dr. Dmitrij Rappoport,

    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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  • Patricia O. Yau,

    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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  • Dr. Philip W. Snyder,

    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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  • Prof. Dr. George M. Whitesides

    Corresponding author
    1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
    2. Wyss Institute for Biologically Inspired Engineering, Harvard University, 60 Oxford Street, Cambridge, MA 02138 (USA)
    • Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
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  • The authors thank Dr. Jasmin Mecinovic, Dr. Ramani Ranatunge, Dr. Demetri Moustakas, Dr. Manza Atkinson, Dr. Mohammad Al-Sayah, Dr. Shuji Fujita, and Mr. Jang Hoon Yoon for their technical contributions. This work was supported by the National Science Foundation (CHE-1152196) and the Wyss Institute of Biologically Inspired Engineering. H.L. thanks the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral stipend.

Abstract

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It's the water that matters. Pairs of benzo- and perfluorobenzoarylsulfonamide ligands bind to human carbonic anhydrase with a conserved binding geometry, an enthalpy-driven binding, and indistinguishable binding affinities (see picture). These data support the pervasive theory that the lock-and-key model disregards an important component of binding: the water, which fills the binding pocket of the protein and surrounds the ligand.

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