A Structural Study of Arylacetylenes as Inhibitors of Cytochrome P450

芳基乙炔作为细胞色素 P450 抑制剂的结构研究

• 批准号: 6727044
• 负责人: Cheryl L Klein Stevens
• 金额: $ 11.24万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727044
• 关键词: X ray crystallography; active sites; alkynes; analog; charge coupled device camera; chemical models; chemical structure function; computer simulation; conformation; cytochrome P450; electron density; enzyme inhibitors; laboratory mouse; model design /development; phenanthrene; quantum chemistry; X ray crystallography; active sites; alkynes; analog; charge coupled device camera; chemical models; chemical structure function; computer simulation; conformation; cytochrome P450; electron density; enzyme inhibitors; laboratory mouse; model design /development; phenanthrene; quantum chemistry

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.

这项研究旨在“绘制”一系列芳基乙烯烯的三维结构和电子特征，称为基于机理的P450 1A1、1A2和2B1的机理抑制剂。该映射将包括通过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电位确定的乙炔基的电子特性。为了计算这些数量，将在4-丙尼苯基和2-乙基苯乙烯上收集精心测量的实验X射线衍射数据。这两种化合物均已确定为基于选择性机制的抑制剂，并能够区分P450 1A和1B酶。提出了一系列称为P450酶抑制剂的大量芳基乙烯的分子建模研究。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（空间，静电和亲脂性）之间的关系。 P450 1A1、1A2和2B1的同源模型将基于从蛋白质晶体结构中获得的晶体学信息构建 P450 BM-3，用于探索P450芳基乙烯抑制的机理。