基于分子对接、分子动力学模拟的新型酰胺-膦酸酯类hsEH抑制剂的QSAR研究

QSAR study on novel amide-phosphonate hsEH Inhibitors based on molecular docking and molecular dynamics simulation

结合定量结构-活性相关（QSAR）技术和分子对接、分子动力学（MD）模拟,研究了新型酰胺-膦酸酯类衍生物与可溶性环氧化物水解酶（hsEH）结合的相互作用特征.二维QSAR模型表现出较好的拟合能力和预测能力（r^2=0.942,q2=0.918）,并且模型表明酰胺-膦酸酯类衍生物中C—N键的频数对hsEH活性抑制能力具有重要影响.采用比较分子力场分析方法（CoMFA）和比较分子相似性指数分析方法（CoMSIA）建立了相关性显著、预测能力强的三维QSAR定量模型（CoMFA：r^2=0.986,q2=0.619;CoMSIA：r^2=0.912,q2=0.630）,模型指出疏水作用力、静电作用力和氢键作用力对hsEH活性抑制能力有重要的影响.二维QSAR模型的预测结果更为准确,三维QSAR模型更为直观地表现了由于分子结构差异导致不同的力场效应对预测结果的影响.分子对接结果指出了分子内酰胺基团、膦酸酯基团、以及—NH—分子结构能与氨基酸残基HIS524,ASP335,TYR383,TYR466,GLN384和Trp525形成稳定氢键来增加结合的稳定性,并且小分子受到氢键作用力的同时还受到结合位点疏水残基的强疏水作用力和芳香性π环之间相互吸引的π-π堆积的非共价键作用.分子动力学模拟通过残基结合后的柔性差异变化验证了结合位点分子对接结果的可靠性,结合自由能也为对接作用机制的合理性提供了验证.

The interaction mode and characteristics of the new amide-phosphonate derivatives on human soluble epoxide hydrolase（hsEH）were studied by quantitative structure-activity relationship（QSAR）,molecular docking and molecular dynamics simulation（MD）.The 2D-QSAR model shows the high fitting ability and high predictive ability（r^2=0.942,q2=0.918）.This model shows that the the number of C—N bonds of the amide-phosphonate derivatives are important factors to the inhibit hsEH activity.The 3 D-QSAR model of comparative molecular field analysis（CoMFA）and comparative molecular similarity index analysis（CoMSIA）show a significant correlation and strong ability of prediction（CoMFA：r^2=0.986,q^2=0.619;CoMSIA：r^2=0.912,q2=0.630）,and indicate that the hydrophobic interaction,electrostatic force and hydrogen bond play important roles for the activity inhibitory of hsEH.The prediction results of the 2D-QSAR model are more accurate.The 3D-QSAR model is more intuitive to show the effect of different force field effects on the prediction results due to the molecular structure difference.The molecular docking results indicate that the intramolecular amide groups,phosphonate groups and the—NH— molecular structure can form stable hydrogen bonds with the amino acid residues HIS524,ASP335,TYR383,TYR466,GLN384 and Trp525 to increase the stability of binding,and the hydrogen bond,strong hydrophobic forces at the binding sites of hydrophobic residues,and theπ-πstacking also play important roles.The reliability of the docking results of the binding sites is verified by the molecular dynamics simulation,and the rationality of the docking mechanism is verified by the free energy.