Date Approved

6-13-2024

Embargo Period

6-13-2025

Document Type

Thesis

Degree Name

Master of Science (M.S.) in Pharmaceutical Science

Department

Chemistry and Biochemistry

College

College of Science & Mathematics

Advisor

Chun Wu, Ph.D.

Committee Member 1

Gregory A. Caputo Ph. D.

Committee Member 2

Kandalam V. Ramanujachary Ph. D

Keywords

Biochemistry; Biophysics; Computer aided drug design; Molecular Dynamics; Molecular mechanics; Protein kinetics

Subject(s)

Drugs--Design

Disciplines

Medicinal-Pharmaceutical Chemistry | Pharmacy and Pharmaceutical Sciences

Abstract

Chapter 1 introduces computational strategies in computer aided drug design (CADD), focusing on physics-based methodologies to enhance drug discovery. This chapter also discusses the theoretical foundations and practical applications of molecular dynamics (MD) simulations including free energy and stochastic kinetic analysis. In Chapter 2, CADD methods lead to development of inhibitors targeting the RNA Dependent RNA Polymerase (RdRP) of SARS-CoV-2. Inspired by the nucleotide inhibitor Molnupiravir, we aim to design a combinatorial library of 72 novel inhibitors capable of impeding a dual threat inhibition mechanism inducing lethal mutations along with stalling viral replication with specific selectivity to RdRp over Human Polymerase II. In Chapter 3, we concentrate on the characterization of MmpL3, a crucial Resistance Nodulation Division (RND) transporter in MtB. Through molecular dynamics simulations, we gain a comprehensive understanding of MmpL3's structural dynamics and conformational functionality. A significant aspect of this chapter involves investigating the inhibition mechanism of SQ109, an Anti-tuberculosis drug, with a specific focus on understanding it’s the conformational states of MmpL3 and allosteric inhibition effects induced by SQ109.

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Available for download on Friday, June 13, 2025

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