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Rational Design of Small-Molecule Inhibitors of Protein-Protein Interactions: Application to the Oncogenic c-Myc/Max Interaction

Meireles, Lidio Marx Carvalho (2011) Rational Design of Small-Molecule Inhibitors of Protein-Protein Interactions: Application to the Oncogenic c-Myc/Max Interaction. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Protein-protein interactions (PPIs) constitute an emerging class of targets for pharmaceutical intervention pursued by both industry and academia. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in today's drug discovery. This dissertation describes novel computational approaches developed to facilitate the discovery/design of small-molecule inhibitors of PPIs, using the oncogenic c-Myc/Max interaction as a case study.First, we critically review current approaches and limitations to the discovery of small-molecule inhibitors of PPIs and we provide examples from the literature.Second, we examine the role of protein flexibility in molecular recognition and binding, and we review recent advances in the application of Elastic Network Models (ENMs) to modeling the global conformational changes of proteins observed upon ligand binding. The agreement between predicted soft modes of motions and structural changes experimentally observed upon ligand binding supports the view that ligand binding is facilitated, if not enabled, by the intrinsic (pre-existing) motions thermally accessible to the protein in the unliganded form.Third, we develop a new method for generating models of the bioactive conformations of molecules in the absence of protein structure, by identifying a set of conformations (from different molecules) that are most mutually similar in terms of both their shape and chemical features. We show how to solve the problem using an Integer Linear Programming formulation of the maximum-edge weight clique problem. In addition, we present the application of the method to known c-Myc/Max inhibitors.Fourth, we propose an innovative methodology for molecular mimicry design. We show how the structure of the c-Myc/Max complex was exploited to designing compounds that mimic the binding interactions that Max makes with the leucine zipper domain of c-Myc.In summary, the approaches described in this dissertation constitute important contributions to the fields of computational biology and computer-aided drug discovery, which combine biophysical insights and computational methods to expedite the discovery of novel inhibitors of PPIs.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Meireles, Lidio Marx Carvalholmm85@pitt.edu
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairBahar, Ivetbahar@pitt.edu
    Committee CoChairMustata, Gabrielagmustata@pitt.edu
    Committee MemberChennubhotla, Chakrachakracs@pitt.edu
    Committee MemberProchownik, Edwardprochownikev@upmc.edu
    Committee MemberRule, Gordonrule@andrew.cmu.edu
    Title: Rational Design of Small-Molecule Inhibitors of Protein-Protein Interactions: Application to the Oncogenic c-Myc/Max Interaction
    Status: Unpublished
    Abstract: Protein-protein interactions (PPIs) constitute an emerging class of targets for pharmaceutical intervention pursued by both industry and academia. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in today's drug discovery. This dissertation describes novel computational approaches developed to facilitate the discovery/design of small-molecule inhibitors of PPIs, using the oncogenic c-Myc/Max interaction as a case study.First, we critically review current approaches and limitations to the discovery of small-molecule inhibitors of PPIs and we provide examples from the literature.Second, we examine the role of protein flexibility in molecular recognition and binding, and we review recent advances in the application of Elastic Network Models (ENMs) to modeling the global conformational changes of proteins observed upon ligand binding. The agreement between predicted soft modes of motions and structural changes experimentally observed upon ligand binding supports the view that ligand binding is facilitated, if not enabled, by the intrinsic (pre-existing) motions thermally accessible to the protein in the unliganded form.Third, we develop a new method for generating models of the bioactive conformations of molecules in the absence of protein structure, by identifying a set of conformations (from different molecules) that are most mutually similar in terms of both their shape and chemical features. We show how to solve the problem using an Integer Linear Programming formulation of the maximum-edge weight clique problem. In addition, we present the application of the method to known c-Myc/Max inhibitors.Fourth, we propose an innovative methodology for molecular mimicry design. We show how the structure of the c-Myc/Max complex was exploited to designing compounds that mimic the binding interactions that Max makes with the leucine zipper domain of c-Myc.In summary, the approaches described in this dissertation constitute important contributions to the fields of computational biology and computer-aided drug discovery, which combine biophysical insights and computational methods to expedite the discovery of novel inhibitors of PPIs.
    Date: 07 September 2011
    Date Type: Completion
    Defense Date: 26 July 2011
    Approval Date: 07 September 2011
    Submission Date: 04 August 2011
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-08042011-233540
    Uncontrolled Keywords: drug design; drug discovery; oncogene; protein-protein interactions; small-molecule inhibitors
    Schools and Programs: School of Medicine > Computational Biology
    Date Deposited: 10 Nov 2011 14:57
    Last Modified: 11 Jun 2012 13:02
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-08042011-233540/, etd-08042011-233540

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