Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
J Comput Chem. 2010 Jul 15;31(9):1822-31. doi: 10.1002/jcc.21455.
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.
已经对 CYP2A6 及其萘抑制剂进行了计算研究，以探索有助于结合特异性的关键分子特征。通过将这些化合物对接（FlexX）到酶的活性部位，获得了分子生物活性取向。然后使用密度泛函理论方法进一步优化分子结构，并进行分子亲脂性势能（MLP）和分子静电势（MEP）分析。最小 MLP、最小 MEP 和能带隙能量（最高占据分子轨道和最低未占据分子轨道之间的能量差）与抑制活性（pIC（50））呈高度相关性，表明它们在驱动抑制剂采用适当的生物活性构象方面起着重要作用，该构象定向于 CYP2A6 酶的活性部位。MLP、MEP 和轨道能量的差异被确定为决定这一系列化合物与 CYP2A6 结合特异性和随之而来的抑制作用的关键特征。此外，对接、MLP 和 MEP 分析的组合使用也被证明是深入了解 CYP2A6 与其抑制剂之间相互作用的良好尝试。
