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)有选择性的CtytoChrome P450抑制剂可能被用作抗启动剂和用于改变癌症促进和进展阶段的试剂。这项研究旨在绘制一系列芳香烃的三维结构和电子特征图，这些芳香烃已知作为细胞色素P450亚型1A1、1A2、2A6和2B1的基于机制的抑制剂。该图谱将包括由X射线结晶学技术确定的分子的整体几何形状。它还将包括由原子净电荷、电子密度分布和静电势确定的乙炔基团的电子特征。此外，该项目还将包括一系列芳香烃的分子模拟研究，这些芳香烃被认为是P450酶的抑制剂。这项研究将包括3D-QSAR和药效团图谱的测定。将这些抑制剂对接到P450的1A2和2A6的晶体结构的活性部位，以及P450的1A1和2B1的同源模型，将被用来探索芳香乙炔抑制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.