This study is designed to """"""""map"""""""" the three-dimensional structure and electronic character of a series of arylacetylenes known to act as mechanism based inhibitors of P450 1A1, 1A2, 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 group determined by net atomic charges, electron density distributions, and electrostatic potentials. To calculate these quantities, carefully measured experimental x-ray diffraction data will be collected on 4-propynylbiphenyl and 2-ethynylpyrene. Both of these compounds have been determined to be selective mechanism based inhibitors and able to discriminate between P450 1A and 1B enzymes. A molecular modeling study of a large series of arylacetylenes known to act as inhibitors of P450 enzymes is proposed. This study will include determination of the 3D-QSAR and a pharmacophore map. A CoMFA study will be used to extract the relationship between the mechanism based inhibition and the three-dimensional features (steric, electrostatic, and lipophilic) of the molecules. A homology model of P450 1A1, 1A2, and 2B1 will be built based on crystallographic information available from the protein crystal structure of P450 BM-3 and used to explore the mechanism of arylacetylene inhibition of P450.
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