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    Inhibition of protein interactions: co-crystalized protein–protein interfaces are nearly as good as holo proteins in rigid-body ligand docking

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    Belkin_2018.pdf (1.064Mb)
    Issue Date
    2018-07-12
    Author
    Belkin, Saveliy
    Kundrotas, Petras J.
    Vakser, Ilya A.
    Publisher
    Springer International Publishing
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    © Springer International Publishing AG, part of Springer Nature 2018
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    Abstract
    Modulating protein interaction pathways may lead to the cure of many diseases. Known protein–protein inhibitors bind to large pockets on the protein–protein interface. Such large pockets are detected also in the protein–protein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation. The conformational change on the protein interface upon binding to the other protein results in a pocket employed by the ligand when it binds to that interface. This proof-of-concept study suggests that rather than using computational pocket-opening procedures, one can opt for an experimentally determined structure of the target co-crystallized protein–protein complex as a starting point for drug design.
    URI
    http://hdl.handle.net/1808/29736
    DOI
    https://doi.org/10.1007/s10822-018-0124-z
    Collections
    • Molecular Biosciences Scholarly Works [573]
    Citation
    Belkin, S., Kundrotas, P. J., & Vakser, I. A. (2018). Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking. Journal of computer-aided molecular design, 32(7), 769–779. doi:10.1007/s10822-018-0124-z

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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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