高等学校化学学报Issue(12)：2605-2611,7.DOI:10.7503/cjcu20140713
CYP2 C9酶与Warfarin结合模型的立体选择性理论研究
Theoretical Studies on the Substrate Binding Mode and Regioselectivity of Human CYP2 C9 with S-and R-Warfarin
摘要
Abstract
Cytochrome P450(CYP)2C9, a member of the 2C subfamily of CYPs, plays important role in the oxidative metabolism of amount of current clinical drugs. CYP2C9 shows the substrate regioselectivity toward Warfarin. The currently available X-ray structure of CYP2C9-S-Warfarin complex(PDB ID:1OG5) shows a non-productive orientation of the S-Warfarin bound in the active site of CYP2 C9. A series of investigations including automatic docking, molecular dynamics(MD) simulation, combined with tunnel analysis and the MM-GB/SA calculation, identified a 6-, 7-hydroxylation state of the substrate binding mode in the re-dock complex structure, as well as the “metastable state” in the crystal structure. In addition, the comparison of the CYP2 C9 binding to S-and R-Warfarin shows the structural features relevant to the substrate regioselectivity of CYP2C9. According to 100 ns MD simulations, the key residues that, in the active binding site, particular-ly Phe cluster residues, are proposed to play indispensable role in the stabilization of substrates. The investiga-tion of CYP2 C9-substrate binding modes provides detailed insights into the structural features of human CYP2C9 toward Warfarin at the atomic level, and will be valuable information for drug development.关键词
分子对接/分子动力学模拟/细胞色素P450/结合自由能分析/CYP2C9酶和S-Warfarin复合物Key words
Molecular docking/Molecular dynamics simulation/Cytochrome P450/MM-GB/SA/CYP2 C9 and Warfarin complex分类
化学化工引用本文复制引用
吴云剑,崔颖璐,郑清川,张红星..CYP2 C9酶与Warfarin结合模型的立体选择性理论研究[J].高等学校化学学报,2014,(12):2605-2611,7.基金项目
国家自然科学基金(批准号:21273095)资助.覮 Supported by the National Natural Science Foundation of China(No.21273095) （批准号:21273095）
