Date Approved

2-17-2021

Embargo Period

2-19-2021

Document Type

Thesis

Degree Name

M.S. Pharmaceutical Sciences

Department

Chemistry and Biochemistry

College

College of Science & Mathematics

First Advisor

Wu, Chun

Second Advisor

Caputo, Gregory

Third Advisor

Keck, Thomas

Keywords

G protein, GPCR, Molecular dynamics, Xanthohumol

Subject(s)

Drugs--Design; Chemistry--Computer simulation

Disciplines

Medicinal-Pharmaceutical Chemistry

Abstract

The overarching purpose of this document is to use Computer-aided drug design and Molecular dynamic simulations to better understand elusive drug-receptor interactions, as well as various types of inter-receptor signaling. Chapter One introduces the theory and importance of Computer-aided drug design and the methodology used in both Chapters Two and Three.

Chapter Two uncovers the relationship between the well-studied ABCB1 transporter and a newly identified drug known as Xanthohumol (XN). XN is compared to a commonly used drug, Doxorubicin (DOX), in this chapter. If the ABCB1 transporter can be properly inhibited, cancer-fighting drugs will be able to stay within the cancer cell and will therefore be more effective. Molecular dynamic simulations are completed and analyzed for both XN and DOX as comparison. It was determined that XN competitively blocks DOX binding and may be a stronger inhibitor than DOX.

Chapter Three uses MD simulations to study GPCR signaling when bound to an agonist or antagonist and when unbound. Through MD simulation and analysis, it was determined that the alpha subunit plays an important role in GPCR- G-protein activation. Using MM-GBSA, RMSF/D, and other various analyses, various aspects of GPCR-G-protein activation were uncovered within this chapter.

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