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    Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities

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    Zhao_2014.pdf (2.389Mb)
    Issue Date
    2014-01-27
    Author
    Moroni, Elisabetta
    Zhao, Huiping
    Blagg, Brian S. J.
    Colombo, Giorgio
    Publisher
    American Chemical Society
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ci4005767.
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    Abstract
    The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated anti-proliferative activity at ~150 nanomolar concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.
    URI
    http://hdl.handle.net/1808/24228
    DOI
    https://doi.org/10.1021/ci4005767
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Moroni, E., Zhao, H., Blagg, B. S. J., & Colombo, G. (2014). Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities. Journal of Chemical Information and Modeling, 54(1), 195–208. http://doi.org/10.1021/ci4005767

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    KU Libraries
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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