Date of Completion

Spring 5-1-2021

Thesis Advisor(s)

Paul Ross Wilderman

Honors Major

Doctor of Pharmacy


Biochemistry, Biophysics, and Structural Biology | Chemicals and Drugs | Pharmacy and Pharmaceutical Sciences


Bupropion is an antidepressant and smoking cessation aid that is extensively metabolized by cytochrome P450 (CYP) 2B6. It is a highly lipophilic chiral drug that undergoes stereoselective metabolism with preference for the (S)-enantiomer. Despite chemical reasons for why bupropion can be metabolized by other CYP isozymes, clinically, bupropion is preferentially metabolized by CYP2B6, and at certain concentrations, CYP2E1, CYP2C19, and CYP3A4. A computational analysis with simulated molecular docking was performed using two different scoring algorithms to analyze the specific amino acid interactions between bupropion and various CYP isozymes. Trials were run using one stereoisomer of bupropion (R- or S-) and a panel of nine human drug metabolizing CYP enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The location of ligand binding was observed, and interactions between the ligand and enzyme active site residues and heme group were defined as residues within 5 Å of the ligand. In silico docking experiments revealed that in some isozymes, bupropion did not bind close enough to the heme for metabolism (CYP2C9), had the site of CYP enzyme metabolism away from the heme iron (CYP2D6), had many steric clashes (CYP2E1), or had a mix of these issues (CYP2C19). However, differences in binding alone do not fully explain the CYP2B6 selective bupropion metabolism.