Aromatic Acetylenes as Inhibitors of Cytochrome P450, a Structural Study

芳香乙炔作为细胞色素 P450 抑制剂的结构研究

• 批准号: 7496250
• 负责人: Cheryl L Klein Stevens
• 金额: $ 20.36万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496250
• 关键词: Acetylene; Active Sites; Amino Acid Sequence; Area; Bispecific Antibody 2B1; Characteristics; Charge; Coumarins; Cytochrome P450; Data; Development; Diagnostic Neoplasm Staging; Docking; Electronics; Electrostatics; Enzymes; Ethers; Ethyl Ether; Homology Modeling; Maps; Measures; Object Attachment; Proteins; Research; Research Support; Roentgen Rays; Score; Series; Source; Structure; Techniques; X ray diffraction analysis; X-Ray Diffraction; alpha benzopyrone; base; density; design; electron density; enzyme model; inhibitor/antagonist; molecular modeling; pharmacophore; three dimensional structure

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.

描述（由申请人提供）：对某些 P450 酶（1A1、1A2、2A6 和 2B1）具有选择性的细胞色素 P450 抑制剂有可能用作抗引发剂以及用于改变癌症促进和进展阶段的药物。本研究旨在“绘制”一系列已知作为细胞色素 P450 亚型 1A1、1A2、2A6 和 2B1 抑制剂的芳香族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。此外，该项目还将包括对已知可作为 P450 酶抑制剂的一系列芳香族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。将这些抑制剂对接至P450s 1A2和2A6晶体结构的活性位点，以及P450s 1A1和2B1的同源模型，将用于探索芳香族乙炔抑制P450的机制。