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SCDMDG presents:

Characterization of Substrate/Inhibitor Binding to Drug-Metabolizing Cytochrome P450 Monooxygenases using X-ray Crystallography

Eric Johnson, Ph.D
Department of Molecular and Experimental Medicine
The Scripps Research Institute
10550 N Torrey Pines Rd
La Jolla, California

Cytochrome P450 monooxygenases determine the rate of clearance for many drugs, and metabolic clearance by P450s can limit the bioavailability and efficacy of new molecular entities. Although each of the major drug-metabolizing P450s exhibits a broad capacity to recognize structurally diverse compounds, they make distinct contributions to drug clearance that reflect underlying structural differences between the enzymes that shape substrate and inhibitor recognition. This is evident from comparative analyses of x-ray crystal structures for the predominant P450s in human liver, 3A4, 1A2, 2C9, 2C19, 2C8, 2D6, 2A6, 2A13 and 2E1, which contribute substantially to drug clearance. The largely hydrophobic substrate binding cavities differ greatly in size from >1500 3 for 3A4 and 2C8 to <300 3 for 2A6 and 2E1. Although trends in substrate profiles for each enzyme generally correspond well to cavity volumes, it is also clear that relatively small substrates can be efficiently oxidized by enzymes with much larger active site cavities. This reflects several mechanisms that include specific interactions that position the molecule appropriately for catalysis, differential changes in active site hydration, and occupancy of the active site by more than one substrate molecule such that one molecule facilitates oxidation of the other. Conversely, structures obtained for individual P450s complexed with structurally distinct substrates demonstrate active site plasticity, which can adapt in response to specific substrates. Together, these structures provide a basis for modeling the interactions of P450s with compounds of interest.

Date: Tuesday, September 30, 2008 – 5:00 p.m. (Buffet), 7:00 p.m. (Presentation)
Location: Salk Institute for Biological Studies
Price: $15 Advance Registration, $15 At the Door (includes buffet dinner and soft drinks/beer/wine)

Space is Limited — Register Early to Guarantee Your Attendance!


Prior presentations:

Speaker Topic Date
Dr. Kenneth E. Thummel, PhD Regulation Of Intestinal CYP3A By VDR: Implications And Safety Of Oral Therapeutics May 7, 2008
Dr. Anthony Lu, PhD Why Is The Liver Microsomal Cytochrome P450 Such A Versatile And Unique Enzyme? September 12, 2007
Dr. Scott Obach, PhD Leveraging ADME Data In Metabolites In Safety Testing (MIST) April 18, 2007
Dr. Sidney Nelson, PhD Drug Metabolism and Chemical Structural Alerts September 27, 2006
Richard B. Kim, MD Relevance and Utility of Transporters to Drug Discovery and Development September 21, 2005
Dr. Frederick P. Guengerich, Ph.D. Human Cytochrome P450 2A6 as a Case History:  Flavors, Smoke, Blue Roses, New Drugs & Basics of a P450 April 27, 2005
Dr. Leslie Benet, Ph.D. Predicting Drug Disposition via Application of BCS: Transport/Absorption/Elimination Interplay and BDDCS September 29, 2004
Dr. Christopher A. Lipinski, Ph.D. ADME/Tox: How Low Can You Go And How Do You Recover? April 21, 2004


Our September 2008 meeting is generously sponsored by:

Takeda San Diego CellzDirect Invitrogen Corporation BD Biosciences

Click here for a printable flyer.