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

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.

本研究旨在“绘制”一系列已知作为 P450 1A1、1A2 和 2B1 机制抑制剂的芳基乙炔的三维结构和电子特征。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。它还将包括由净原子电荷、电子密度分布和静电势确定的乙炔基团的电子特性。为了计算这些量，将收集 4-丙炔基联苯和 2-乙炔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基于选择性机制的抑制剂，并且能够区分 P450 1A 和 1B 酶。提出了对大量已知可作为 P450 酶抑制剂的芳基乙炔进行分子模型研究。这项研究将包括 3D-QSAR 和药效团图的测定。 CoMFA 研究将用于提取基于抑制的机制与分子的三维特征（空间、静电和亲脂性）之间的关系。将根据从蛋白质晶体结构获得的晶体学信息构建 P450 1A1、1A2 和 2B1 的同源模型 P450 BM-3并用于探索芳基乙炔抑制P450的机制。