乙酰胆碱酯酶AChE与1,7-二氮杂咔唑抑制剂的作用机理的分子动力学模拟

通过分子对接、分子动力学（MD）模拟以及成键自由能分析方法，从原子水平上模拟研究了3种1，7-二氮杂咔唑衍生物（分别记为M1、M2和M3）与AChE的结合模式及相互作用机理，分析和讨论了研究体系的静电相互作用和范德华相互作用（vdW）。用MM-PBSA方法计算的3种抑制剂与AChE之间的结合自由能与抑制剂的实验生物活性数据（IC₅₀值）相对应。分析结果表明，残基S286与抑制剂之间形成的氢键作用有利于抑制剂与AChE之间的结合。范德华相互作用，尤其是抑制剂与关键残基W279和Y334的作用，对抑制剂与AChE之间的结合自由能有较大的贡献，在区分抑制剂M1（或M2）和M3的生物活性上发挥着重要的作用。

Interaction Mechanism Between AChE and 1, 7-Diazacarbazole Inhibitors Based on Molecular Dynamics Simulations

The molecular docking, molecular dynamics (MD) simulation, and binding free energy analysis are used to gain the insight into the binding mechanism of three 1,7-diazacarbazole derivatives (marked as M1, M2, and M3, respectively) with AChE at the atom level. The electrostatic and van der Waals (vdW) interactions of the three inhibitors with AChE are analyzed and discussed. The ranking of the computed binding free energies based on MM-PBSA method is consistent with the ranking of experimental bioactivities for the three inhibitors. The hydrogen-bond interactions of the inhibitors with S286 are favorable to the binding affinity of inhibitors to AChE. The van der Waals interactions, especially the key contacts with W279 and Y334 have larger contributions to the binding free energy and play an important role in distinguishing the bioactivities of M1(or M2) and M3.