Thursday, October 2, 2008
Salon B and C (The Peabody Little Rock)

Computational Docking Studies of Nitroanisoles and Nitrophenols with CYP2E1

Dax Demaree, Ouachita Baptist University, Arkadelphia, AR, Marty Perry, Ouachita Baptist University, Arkadelphia, AR, and Grover P. Miller, University of Arkansas for Medical Sciences, Little Rock, AR.

CYP2E1, a mammalian cytochrome P450, has been shown to oxidize xenobiotic substrates, e.g. drugs, environmental contaminants, and food additives, via a non-hyperbolic kinetic mechanism. These complex reaction kinetics likely reflect the contributions of two binding sites, whose occupancy can impact the biological role of CYP2E1. Studying CYP2E1 with computational tools and experimental kinetic data, it is possible to predict non-hyperbolic reaction kinetics for CYP2E1 complexes with substrates. Sybyl7.2 from Tripos, Inc. was used to simulate the interaction between various substrates, specifically nitroanisoles and nitrophenols, and CYP2E1 binding sites. The detoxification pathway of nitroanisoles to nitrophenols is critical in the elimination of these foreign substances from the body. Surflex-Dock 2.0, a rigid docking method, was initially used to dock substrates in the binding site of CYP2E1. Molecular dynamics simulations were also conducted on each of the substrates as they moved through the access channel toward the active site near the heme group. Final complex geometries from each method yield different results. While Surflex-Dock can rapidly dock and score substrates, the most stable conformation is not always conducive to the necessary oxidation process. Results from the molecular dynamics simulations, however, are much more promising.