三重再摄取抑制剂从单胺转运体解离的拉伸分子动力学模拟研究

目的 研究三重再摄取抑制剂(triple reuptake inhibitors，TRIs)与人类单胺转运体(human monoamine transporters，hMATs)的解离机制。方法 采用拉伸分子动力学的方法模拟3个TRIs从hSERT、hNET和hDAT主要结合位点解离的动态过程；通过计算解离过程中施加的外力随模拟时间的变化，分析抑制剂解离过程中重要的蛋白-配体间的相互作用；最后通过Jarzynski方程的二次累积展开式计算抑制剂在3种转运蛋白的平均力势。结果 力谱图曲线表明影响TRIs解离的残基在单胺转运蛋白上的分布主要如下：跨膜区域(TM1b、TM3、TM6a、TM10)和胞外Loop区域(EL2、EL4、EL5、EL6)，其中主要结合口袋附近的残基极大地阻碍TRIs的解离。比较每个体系的平均力势数值，结果表明EB1020相比NS2359和SEP225289更容易从蛋白中解离。结论 本研究从原子水平揭示了hMATs与TRIs结合-解离机制，为基于结构的选择性抗抑郁药物设计提供了理论依据。

Study on the Unbinding of Triple Reuptake Inhibitor from Monoamine Transporters by Steered Molecular Dynamics Simulations

OBJECTIVE To investigate the unbinding mechanism between triple reuptake inhibitors(TRIs) and human monoamine transporters(hMATs). METHODS Steered molecular dynamics was used to explore the unbinding process of three inhibitors from hSERT, hNET and hDAT. The important protein-ligand interactions during dissociation were analyzed by calculating the external force-time profiles. Finally, the results of potential of mean force of the three inhibitors in each transporter were calculated by using the second cumulant expansion of Jarzynski’s equality. RESULTS The force-time curve indicated that residues located in transmembrane domains(TM1b, TM3, TM6a and TM10) and extracellular loops domains(EL2, EL4, EL5 and EL6) were mainly involved in the ligand unbinding. The residues were located on the center binding site of protein could greatly hinder ligand dissociation. The average power potential of each system was computed and the result denoted that the dissociation of EB1020 from the hMATs was easier than that of NS2359 and SEP225289. CONCLUSION This study reveals the unbinding dissociation mechanism of hMATs and TRIs at the atomic level, which provides a theoretical basis for structure-based antidepressant drug design with higher potency and selectivity.