Date Approved

9-1-2016

Embargo Period

9-1-2016

Document Type

Thesis

Degree Name

MS Pharmaceutical Sciences

Department

Chemistry & Biochemistry

College

College of Science & Mathematics

Advisor

Wu, Chun

Committee Member 1

Jonnalagadda, Subash

Committee Member 2

Perez, Lark

Keywords

homology modeling, MD simulation

Subject(s)

Drugs--Design; Bioinformatics; Ligands (Biochemistry)

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

Morphine prescribing is limited by its high addiction tendency and other serious effects. Recent animal’s biological studies on Mu 6TM splice variants, which mainly include G1, G2 and Mu3, supported a high safety and potency profiles of IBNtxA as potential alternative of Morphine. Nevertheless, there is no high-resolution structures of these 6TM variants, and the detailed structural features and dynamic characteristics of these splice variants remain elusive. We applied homology modeling and MD simulation to probe the structural, dynamic and ligand binding differences between the wild type (7TM) and two major truncated 6TM variants (G1 and G2). MD results underscored important structural and dynamic differences between these receptors as well as prioritized ligand affinity toward each receptor. The second project in this thesis involves in silico analysis of mutational basis of Amsacrine resistance. Both R487K and E571K mutations were studied. MD results indicated significant weakening of Amsacrine affinity in two mutants in a consistent manner with the previous biological degree of resistance of two mutants. Additionally, the intercalation loss and ligand ternary complex coordinate changes were also revealed by MD simulation as possible causes of resistance.

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