Reducing CYP-2 liabilities using pharmacophore hypotheses derived from protein structures and inhibitors


Akbar Nayeem and Litai Zhang. Computer-Assisted Drug Design, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543-5400
The CYP-2 family of cytochrome P450s ranks among the most important drug metabolizing CYP isoforms present in human liver, and numerous inhibitory drug interactions of high clinical significance involving CYP 2D6 and 2C9 substrates have been described. With the goal of reducing the liability of drug-drug interactions caused by possible inhibition of CYP 2C9, 2C19 and 2D6, 3D-pharmacophore models for each of these isoforms have been developed using their respective homology models, known substrates, and our in-house inhibitors from BMS. The pharmacophore hypotheses derived from these models are presented and are shown to be useful in understanding the active site of these isozymes. The in-silico models derived thusly are used to triage and prioritize chemical library synthesis and reduce the potential liability of drug-drug interactions caused by CYP-2 family inhibitions.

Advances in Virtual High-Throughput Screening
1:00 PM-2:30 PM, Thursday, August 26, 2004 Pennsylvania Convention Center -- 110A&B, Oral

8:00 PM-10:00 PM, Monday, August 23, 2004 Pennsylvania Convention Center -- Hall D, Sci-Mix

Division of Chemical Information

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004