A Structural Study of Arylacetylenes as Inhibitors of Cytochrome P450

本研究旨在“绘制”一系列芳基乙炔的三维结构和电子特征，这些芳基乙炔被称为P450 1A1, 1A2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。为了计算这些量，将收集4-丙基联苯和2-乙基芘的仔细测量的实验x射线衍射数据。这两种化合物已被确定为选择性机制抑制剂，能够区分P450 1A和1B酶。提出了一项分子模型研究的大系列芳基乙炔已知作为抑制剂的P450酶。这项研究将包括确定3D-QSAR和药效团图。CoMFA研究将用于提取基于机理的抑制与分子的三维特征（立体、静电和亲脂性）之间的关系。基于蛋白质晶体结构的晶体学信息，构建P450 1A1、1A2和2B1的同源性模型

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.