Department of Medicinal Chemistry

Research Interests

Drug design and metabolism; Structure/function of cytochromes P450; Inhibition of cytochrome P450 enzymes for the prevention and treatment of disease, especially lung and prostate cancer

While most enzymes are very specific for a single substrate, a few are much more versatile. The main interest of the Scott laboratory involves the ability of cytochromes P450 to both bind and metabolize a number of chemicals that are very different in size, shape, and stereochemistry. Within an organism, the presence of a set of these multi-tasking enzymes is largely responsible for the ability to eliminate foreign chemicals including drugs, environmental substances, and carcinogens. Introduction to Cytochromes P450

X-ray structure of cytochrome P450 2E1

Major questions include:

• How does the three-dimensional structure of a cytochrome P450 recognize, bind, and metabolize multiple chemically diverse substrates?
• By what mechanism can two different P450s act on a common substrate but differentiate between other chemicals that only one of them can metabolize?
• How do selective inhibitors interact with the protein structure in these versatile enzymes?
• How can we use this knowledge to advance human health by preventing disease, treating disease, or predicting adverse drug-drug-interactions?

APPLICATIONS TO HUMAN DISEASE

Tobacco-related lung cancer

Cytochrome P450 2A13 (CYP2A13) acts on a ring-opened form of nicotine to clear it from the body, but in the process creates two agents that cause lung cancer. Inhibition of CYP2A13 activity is an approach to reduce lung cancer initiation in those who cannot or will not give up exposure to nicotine. We are developing compounds that selectively inhibit CYP2A13 and testing them as chemopreventative agents for tobacco-associated lung cancer.

Inhibition of cytochrome P450 2A13 is a potential new method for preventing lung cancer in smokers

Prostate and Breast Cancer

Cytochrome P450 17A1 (CYP17A1) generates androgen steroid hormones. While androgens are a key part of masculine physiology in the absence of disease, androgens support the growth of prostate cancer, particularly metastatic prostate cancer. Research in the Scott lab is determining how CYP17A1 performs hydroxylation and lyase reactions and how the lyase reaction can be selectively inhibited to treat prostate cancer without negative side effects on mineralocorticoid and glucocorticoid production. Because estrogens are made from androgens, this approach may also be effective for estrogen-responsive breast cancer.

METHODS

To investigate these and related questions, the laboratory uses methods in:

• molecular biology (site-directed mutagenesis, recombinant protein expression and purification)
• biochemistry (assays of protein function, various spectroscopic methods)
• structural biology (x-ray crystallography and NMR)