点击次数：

论文类型：期刊论文

发表时间：2010-07-15

发表刊物：JOURNAL OF COMPUTATIONAL CHEMISTRY

收录刊物：EI、SCIE、Scopus

卷号：31

期号：9

页面范围：1822-1831

ISSN号：0192-8651

关键字：CYP2A6-ligand interaction; docking; molecular electrostatic potential; molecular lipophilic potential; orbital energies

摘要：A computational investigation has been carried out on CYP2A6 and its naphthalene inhibitors to explore the crucial molecular features contributing to binding specificity. The molecular bioactive orientations were obtained by docking (FlexX) these compounds into the active site of the enzyme. And the density functional theory method was further used to optimize the molecular structures with the subsequent analysis of molecular lipophilic potential (MLP) and molecular electrostatic potential (MEP). The minimal MLPs, minimal MEPs, and the band gap energies (the energy difference between the highest occupied molecular orbital and lowest unoccupied molecular orbital) showed high correlations with the inhibition activities (pIC(50)s), illustrating their significant roles in driving the inhibitor to adopt an appropriate bioactive conformation oriented in the active site of CYP2A6 enzyme. The differences in MLPs, MEPs, and the orbital energies have been identified as key features in determining the binding specificity of this series of compounds to CYP2A6 and the consequent inhibitory effects. In addition, the combinational use of the docking, MLP and MEP analysis is also demonstrated as a good attempt to gain an insight into the interaction between CYP2A6 and its inhibitors. (c) 2010 Wiley Periodicals, Inc. J Comput Chem 31: 1822-1831, 2010