Aromatic Acetylenes as Inhibitors of Cytochrome P450, a Structural Study

描述（由申请人提供）：对某些P450酶（1A 1、1A 2、2A 6和2B 1）具有选择性的细胞色素P450抑制剂可能用作抗起始剂和用于改变癌症促进和进展阶段的药物。本研究的目的是“映射”的三维结构和电子特性的一系列芳香乙炔已知作为基于机制的抑制剂细胞色素P450亚型1A 1，1A 2，2A 6和2B 1。映射将包括由X射线晶体学技术确定的分子的整体几何形状。它还将包括乙炔基团的电子特性，由净原子电荷，电子密度分布和静电势决定。此外，该项目还将包括一系列已知作为P450酶抑制剂的芳香族乙炔的分子模拟研究。本研究将包括测定3D-QSAR和药效团图谱。将这些抑制剂对接到P450 1A 2和2A 6晶体结构的活性位点，以及P450 1A 1和2B 1的同源模型，将用于探索芳香族乙炔抑制P450的机制。

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.