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Dissertation Defense: A Tale of Two Cities: Merging Biology with Chemistry for Drug Design
May 18, 2018 @ 2:00 pm - 3:00 pm
A Tale of Two Cities: Merging Biology with Chemistry for Drug Design
Eric Samuels, PhD Candidate
Friday, May 18, 2018
2:00 PM – 3:00 PM
Natural Sciences I, Room 1114
Cytochrome P450 represents a superfamily of heme-containing oxidase enzymes responsible for transmuting xenobiotics into more water-soluble compounds. Amongst the cytochrome P450 isoforms, CYP3A4 is the most profuse, and one of the most clinically relevant xenobiotic metabolizing enzymes in humans. Moreover, CYP3A4 is the most chemically versatile P450, with the ability to oxidize a variety of molecules ranging in size and chemical structure. In addition to drugs, CYP3A4 is involved in the transformation of toxins, environmental pollutants, and carcinogens. Variations in expression and activity of CYP3A4 can greatly affect drug efficacy or toxicity. Additionally, various synthetic or naturally derived agents such as furanocoumarin derivatives can either enhance or inhibit CYP3A4 activity. Although inhibition of CYP3A4 can result in undesirable drug toxicity and/or drug-drug interactions, carefully controlled inhibition can be exploited to increase the bioavailability of drugs that would otherwise be rapidly metabolized. Controlled inhibition is already being exploited in HIV and HCV combination treatment with ritonavir. Initially designed as an HIV protease inhibitor, ritonavir was later found to be an effective CYP3A4 inhibitor. However, neither ritonavir, nor its derivatives were developed using pharmacophore models, rational design, or CYP3A4 crystal structures. Therefore, little is understood on the mechanism of inhibition. Using the ritonavir-CYP3A4 crystal structure as a guide, a preliminary pharmacophore model of CYP3A4 inhibition was proposed. Through scaffold modification and rational design, the requirements for successful CYP3A4 inhibition are now more clearly understood. To date, several modest, yet highly potent CYP3A4 inhibitors have been developed. Ultimately, these rationally designed pharmacoenhancers may assist in more effective combination treatment and lower drug costs.