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    How proteins bind macrocycles

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    Date Issued
    2014-09
    Publisher Version
    10.1038/nchembio.1584
    Author(s)
    Villar, Elizabeth A.
    Beglov, Dmitri
    Chennamadhavuni, Spandan
    Porco, John A.
    Kozakov, Dima
    Vajda, Sandor
    Whitty, Adrian
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    Permanent Link
    https://hdl.handle.net/2144/26457
    Citation (published version)
    Elizabeth A Villar, Dmitri Beglov, Spandan Chennamadhavuni, John A Porco, Dima Kozakov, Sandor Vajda, Adrian Whitty. 2014. "How proteins bind macrocycles.." Nat Chem Biol, Volume 10, Issue 9, pp. 723 - 731.
    Abstract
    The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.
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    • BU Open Access Articles [3670]
    • CAS: Chemistry: Scholarly Papers [120]
    • ENG: Biomedical Engineering: Scholarly Papers [268]


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