KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Pocket optimization and its application to identify small-molecule inhibitors of protein-protein interactions

    Thumbnail
    View/Open
    Johnson_ku_0099D_14438_DATA_1.pdf (5.704Mb)
    Issue Date
    2016-05-31
    Author
    Johnson, David Keith
    Publisher
    University of Kansas
    Format
    183 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular Biosciences
    Rights
    Copyright held by the author.
    Metadata
    Show full item record
    Abstract
    Because of their ubiquitous nature in many cellular processes, modulating protein-protein interactions offers tremendous therapeutic potential. However, protein-protein interactions remain a difficult class of drug targets, as most protein interaction sites have not evolved to bind small molecules. Indeed, some protein interaction sites are thought to be simply not amenable to binding any small molecule at all. Other sites feature small molecule binding pockets that simply are not present in the unbound or protein-bound conformations, making structure-based drug discovery difficult. Sometimes, inhibitors bind to multiple family members with high affinity, causing toxicity. In this dissertation I seek to address many of these challenges, by developing methodologies to assess the druggability of a target, assess the selectivity of known inhibitors, identify conformations that are sampled uniquely by a single protein, and identify inhibitors of protein-protein interactions. To assess druggability, I developed the “pocket optimization” protocol which uses a biasing potential to create an ensemble of conformations that contain pockets at a specified location on the protein surface. I showed that low-resolution, low energy inhibitor shapes are encoded at druggable sites and sampled through low-energy fluctuations, whereas they are not present at random sites on protein surfaces. To assess selectivity and screen for inhibitors, I developed “exemplars”, representations of a pocket based on the perfect “non-physical” complementary ligand, allowing the comparison of pocket shapes independent of protein sequence. I predicted the selectivity of an array of inhibitors to a related family of proteins by comparing the exemplars from the known small-molecule bound conformation to the ensemble of exemplars from a “pocket optimized” ensemble. I identified distinct conformations that could be targeted for identifying selective inhibitors de novo by comparing ensembles of exemplars from related family members to one another. Finally, I developed a screening protocol that uses the speed of exemplar versus small molecule comparisons to screen very large compound libraries against ensembles of distinct, “pocket optimized” pocket conformations.
    URI
    http://hdl.handle.net/1808/21851
    Collections
    • Molecular Biosciences Dissertations and Theses [182]
    • Dissertations [2980]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    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
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    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
     

     

      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps