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Discovery of Small Molecule Inhibitors of Protein-Protein Interactions

Huang, Yijun (2012) Discovery of Small Molecule Inhibitors of Protein-Protein Interactions. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Protein-protein interactions (PPIs) constitute an emerging class of targets for the next generation of therapeutic intervention. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in drug discovery. Although small molecule PPI inhibitors are highly valuable due to a number of advantages relative to biological agents in terms of production, delivery, titratability and cost, the robust discovery of lead compounds remains a great challenge. Two structure-based drug discovery strategies are described in this work to generate small molecules to target PPIs. A receptor-based drug discovery approach can be applied when an accurate three-dimensional (3D) structure of a specific PPI complex is available. A novel, complementary and transformative approach for the rational design of small molecule inhibitors based on the crystal structure of the p53-Mdm2 complex was developed. This method is based on a tight interplay of structural biology information, the “anchor” concept, efficient chemical synthesis via multicomponent reactions (MCRs), as well as virtual and real screening processes. Applying the method we efficiently discovered several new scaffolds of inhibitors of the p53/Mdm2 interaction with lower micromolar affinity binding to Mdm2, which can serve as starting point for medicinal chemistry optimization. Advantages of our approach include high hit rates and less attrition based on the parallel discovery of multiple scaffolds, built-in optimization pathways using efficient MCRs, and fast generation of potential lead compounds. Potential anticancer drug candidates were identified by biochemical assays, co-crystallization, cell based assays, as well as further preclinical evaluations (solubility, metabolism, pharmacokinetics, and xenograft studies). A ligand-based drug discovery approach was explored since PPIs are critically dependent on “anchor” residues, which can serve as the pharmacophore model for small molecules. Multicomponent reactions were employed for design of novel scaffolds and DOS of drug-like compounds, since hit identification of PPI inhibitors via traditional approaches such as high throughput screening (HTS) is fundamentally limited by chemotypes present in the library collections. Novel and diverse scaffolds based on the privileged structures (1,4-benzodiazepines, 1,4-thienodiazepines) and “anchor” residues, which can be accessible from multicomponent reactions, were designed and synthesized. Compared with conventional methods, these approaches are advantageous to generate small molecules targeting PPIs in terms of efficiency, diversity, and economy. In summary, the approaches described in this dissertation constitute important contributions to the fields of medicinal chemistry and structure-based drug discovery, which combine structural insights and ligand design to expedite the discovery of novel small molecule inhibitors of PPIs.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairDoemling, Alexander
    Committee MemberDay, Billy
    Committee MemberGold, Barry
    Committee MemberXie, Xiang-Qun
    Committee MemberKlein-Seetharaman, Judith
    Title: Discovery of Small Molecule Inhibitors of Protein-Protein Interactions
    Status: Published
    Abstract: Protein-protein interactions (PPIs) constitute an emerging class of targets for the next generation of therapeutic intervention. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in drug discovery. Although small molecule PPI inhibitors are highly valuable due to a number of advantages relative to biological agents in terms of production, delivery, titratability and cost, the robust discovery of lead compounds remains a great challenge. Two structure-based drug discovery strategies are described in this work to generate small molecules to target PPIs. A receptor-based drug discovery approach can be applied when an accurate three-dimensional (3D) structure of a specific PPI complex is available. A novel, complementary and transformative approach for the rational design of small molecule inhibitors based on the crystal structure of the p53-Mdm2 complex was developed. This method is based on a tight interplay of structural biology information, the “anchor” concept, efficient chemical synthesis via multicomponent reactions (MCRs), as well as virtual and real screening processes. Applying the method we efficiently discovered several new scaffolds of inhibitors of the p53/Mdm2 interaction with lower micromolar affinity binding to Mdm2, which can serve as starting point for medicinal chemistry optimization. Advantages of our approach include high hit rates and less attrition based on the parallel discovery of multiple scaffolds, built-in optimization pathways using efficient MCRs, and fast generation of potential lead compounds. Potential anticancer drug candidates were identified by biochemical assays, co-crystallization, cell based assays, as well as further preclinical evaluations (solubility, metabolism, pharmacokinetics, and xenograft studies). A ligand-based drug discovery approach was explored since PPIs are critically dependent on “anchor” residues, which can serve as the pharmacophore model for small molecules. Multicomponent reactions were employed for design of novel scaffolds and DOS of drug-like compounds, since hit identification of PPI inhibitors via traditional approaches such as high throughput screening (HTS) is fundamentally limited by chemotypes present in the library collections. Novel and diverse scaffolds based on the privileged structures (1,4-benzodiazepines, 1,4-thienodiazepines) and “anchor” residues, which can be accessible from multicomponent reactions, were designed and synthesized. Compared with conventional methods, these approaches are advantageous to generate small molecules targeting PPIs in terms of efficiency, diversity, and economy. In summary, the approaches described in this dissertation constitute important contributions to the fields of medicinal chemistry and structure-based drug discovery, which combine structural insights and ligand design to expedite the discovery of novel small molecule inhibitors of PPIs.
    Date: 16 December 2012
    Date Type: Publication
    Defense Date: 03 November 2011
    Approval Date: 16 December 2011
    Submission Date: 06 December 2011
    Release Date: 16 December 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: Yes
    Number of Pages: 272
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    Uncontrolled Keywords: protein-protein interaction, small molecule inhibitor, multicomponent reaction, p53-Mdm2, structure based drug design, drug discovery
    Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
    Date Deposited: 16 Dec 2011 08:46
    Last Modified: 16 Jul 2014 17:02

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