Date of Award

2015

Document Type

Thesis

Department

Chemistry

First Advisor

Dr. Marty Perry

Second Advisor

Dr. Sarah Hubbard

Third Advisor

Dr. Elizabeth Kelly

Abstract

Pharmaceutical drugs are activated through a process called xenobiotic metabolism. Out of the drugs on the market, 50% are chiral, having two enantiomers. When this drug is metabolized, one of the enantiomers is typically preferred over the other. This unique specificity is thought to be a result of the structure of the protein. Interactions between different residues and the drug being metabolized may affect the movement and orientation of the drug as it moves down the channel of the protein to be oxidized. Further understanding of the metabolism of chiral drugs could possibly be used to predict how new drugs might react within a protein. The results of this study were determined using computational methods. Molecular dynamics in Sybyl-X 1.3 were used to create a simulation of the first step in an oxidation reaction between a specific drug and its target protein. The final product was analyzed to determine the interactions of close residues and calculate their stabilizing energy. The residues with the largest difference in energy between enantiomers were determined for each of the four chosen chiral drugs. This data was compiled with previous research to pinpoint residues possibly responsible for enantiospecificity in CYP2C9.

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