Department of Medicinal Chemistry

Research Interests

Drug design and metabolism; Structure/function of cytochromes P450; Inhibition of cytochrome P450 enzymes

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

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?

X-ray structure of cytochrome P450 2E1

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), and x-ray crystallography. Recently major projects in the lab have involved the human P450s 2A6, 2A13 and 2E1, which constitute a model system for examining enzymes with both overlapping and distinct substrates. The general hypothesis is that comparison of molecular structure and biochemistry across different P450 enzymes will assist in the identification of protein physical and chemical features responsible for differences in their function. These characteristics can then be used to understand and predict substrate specificity and to design selective inhibitors for clinical use.

Application to human disease prevention

One application of the basic biochemistry above is our effort to design a selective inhibitor of cytochrome P450 2A13 for the prevention of lung cancer in smokers. CYP2A13 acts on a ring-opened form of nicotine to clear it from the body. Unfortunately, in the process two carcinogens are created by CYP2A13. These carcinogens interact with DNA to cause lung cancer. Since smokers without a functional copy of the CYP2A13 protein are physiologically normal but less likely to develop lung cancer, we reasoned that inhibition of CYP2A13 activity could be used to safely reduce lung cancer rates in those who cannot or will not give up exposure to nicotine. Working with the KU High Throughput Screening Laboratory and the KU Specialized Chemistry Center we have developed a series of compounds that selectively inhibit CYP2A13, but not the closely related human liver CYP2A6. These compounds are currently being tested to determine if they will make good pharmaceutical agents.

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