Aromatic Acetylenes as Inhibitors of Cytochrome P450, a Structural Study

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DESCRIPTION (provided by applicant): Ctytochrome P450 inhibitors selective for certain P450 enzymes (1A1,1A2, 2A6, and 2B1) could potentially be used as anti-initiation agents and as agents used to modify stages of cancer promotion and progression. This study is designed to "map" the three-dimensional structure and electronic character of a series of aromatic acetylenes known to act as mechanism based inhibitors of cytochrome P450 subtypes 1A1, 1A2, 2A6, and 2B1. The mapping will include the overall geometry of the molecules as determined by X-ray crystallographic techniques. It will also include the electronic characteristics of the acetylene groups determined by net atomic charges, electron density distributions, and electrostatic potentials. In addition, this project will include a molecular modeling study of a large series of aromatic acetylenes known to act as inhibitors of P450 enzymes. This study will include determination of the 3D-QSAR and a pharmacophore map. Docking of these inhibitors into the active sites of the crystal structures of P450s 1A2 and 2A6, as well as homology models of P450s 1A1 and 2B1, will be used to explore the mechanism of P450 inhibition by aromatic acetylenes.