Aromatic Acetylenes as Inhibitors of Cytochrome P450, a Structural Study

描述（由申请人提供）：对某些P450酶（1A1,1A2, 2A6和2B1）选择性的细胞色素P450抑制剂可能潜在地用作抗起始剂和用于改变癌症促进和进展阶段的药物。本研究旨在“绘制”一系列芳香乙炔的三维结构和电子特征，这些芳香乙炔被称为细胞色素P450亚型1A1, 1A2, 2A6和2B1的基于机制的抑制剂。测绘将包括由x射线晶体学技术确定的分子的整体几何形状。它还将包括由净原子电荷、电子密度分布和静电势决定的乙炔基团的电子特性。此外，该项目将包括一个已知作为P450酶抑制剂的大系列芳香乙炔的分子模型研究。这项研究将包括确定3D-QSAR和药效团图。将这些抑制剂对接到P450s 1A2和2A6晶体结构的活性位点，以及P450s 1A1和2B1的同源性模型，将用于探索芳香乙炔对P450的抑制机制。

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.