Khoury, Kareem
(2014)
Small Molecule Inhibitors of Protein-Protein Interactions.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Protein-protein interactions (PPIs) constitute a rising class of targets for the next generation of therapeutic intervention. Though they play a fundamental role in many biological processes and almost all pathological conditions including cancer, diabetes, and autoimmune diseases, , PPIs remain underrepresented in drug discovery. Small molecules are the ideal candidates for PPI inhibitors due to low production cost and better absorption, distribution, metabolism, and excretion (ADME) properties compared to biological agents. Discovering small molecule inhibitors of PPIs has proven to be difficult because of the relatively large contact areas between proteins. Herein are described novel approaches to the chemical synthesis as well as a screening tool which will facilitate the discovery of small molecule inhibitors of PPIs.
Currently, molecules derived from multicomponent reactions (MCRs) are rarely distributed in general screening libraries. The exceptions are special scaffolds, e.g. dihydropyrimidines, whose class includes the blockbuster Ca antagonist, Nifedipine. Interestingly, however, MCR molecules have been frequently described as inhibitors of PPIs. Examples include p53/mdm21,2, Bcl23, HIV-1/gp414, CCR55 and oxytocin antagonists6. These findings support the notion that MCR molecules are especially suitable for mimicking peptides. We have developed a virtual library of scaffolds derived from a diverse set of MCRs which are easily chemically accessible.
In addition, our lab has set forth to discover novel MCRs to add to our virtual library. One such scaffold described in this dissertation is derived from the Ugi-4-component-5-cenetered reaction. A novel amidation of this classic scaffold adds a true four-component reaction to our MCR database. The scope and limitations of this reaction are described in detail allowing for an accurate representation of compounds with a high probability of being synthesized. Various cyclizations of this scaffold are also explored and described in detail.
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 docking approach for the rational design of small molecule inhibitors was developed for our virtual library based on the “anchor” concept. Applying our 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.
In summary, the methods and tools described in this dissertation are important contributions to the fields of medicinal chemistry and structure-based drug discovery because they combine structural insights and ligand design to expedite the discovery of novel small molecule inhibitors of PPIs.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
6 January 2014 |
| Date Type: |
Publication |
| Defense Date: |
7 December 2013 |
| Approval Date: |
6 January 2014 |
| Submission Date: |
5 January 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
229 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Protein-Protein Interactions, p53, MDM2, Multicomponent Reaction Chemistry, MCR, PPI, ANCHOR.QUERY, ANCHOR, Ugi, |
| Date Deposited: |
06 Jan 2014 16:14 |
| Last Modified: |
15 Nov 2016 14:16 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20347 |
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