物理化学学报 >> 2010, Vol. 26 >> Issue (01): 206-214.doi: 10.3866/PKU.WHXB20100117

生物物理化学 上一篇    下一篇

芬太尼类化合物与阿片μ受体相互作用的分子对接与分子动力学模拟

李博, 刘明, 胡文祥   

  1. 首都师范大学物理有机与药物化学研究所, 北京 100048; 首都师范大学生命科学学院, 北京 100048
  • 收稿日期:2009-05-08 修回日期:2009-09-08 发布日期:2009-12-29
  • 通讯作者: 胡文祥 E-mail:huwx66@163.com

Molecular Docking and Molecular Dynamics Simulations of Fentanyl Analogs Binding to μ-Opioid Receptors

LI Bo, LIU Ming, HU Wen-Xiang   

  1. Institute of Physical Organic and Medicinal Chemistry, Capital Normal University, Beijing 100048, P. R. China; College of Life Science, Capital Normal University, Beijing 100048, P. R. China
  • Received:2009-05-08 Revised:2009-09-08 Published:2009-12-29
  • Contact: HU Wen-Xiang E-mail:huwx66@163.com

摘要:

采用分子对接和分子动力学(MD)模拟方法研究了芬太尼类化合物与阿片μ受体的相互作用机制. 先用AutoDock4.0程序将芬太尼类化合物对接到同源模建的阿片μ受体结构中, 再用GROMACS程序包在水溶液体系中分别对12个芬太尼激动剂和阿片μ受体蛋白复合物进行了MD模拟研究, 优化对接复合物的结构, 最后利用MM-PBSA方法, 在APBS程序中计算芬太尼类衍生物与阿片μ受体的结合自由能, 计算出的受体配合物结合常数(Ki)与其实验值吻合较好, 并预测了化合物的活性排序. 结果表明, 复合物蛋白结构与空载受体蛋白结构有较大差异, 特别是胞内区IL2、IL3和跨膜区段TM4骨架构象变化较大, 不同的化合物对受体结构影响也有差异, 活性较好的化合物会增加蛋白特定区域结构的柔性. 芬太尼类化合物可能是通过和受体结合后诱导阿片μ受体构象转变为活性构象, 引起一系列的信号传导激活G蛋白, 从而引发生理效应.

关键词: 分子动力学, 芬太尼, 阿片μ受体, 分子对接

Abstract:

We performed molecular docking andmolecular dynamics (MD) simulations to investigate the interactions between fentanyl analogs and μ-opioid receptors. The AutoDock 4.0 program was used to perform the docking and homology modeling of the μ-opioid receptor structure. MD method as implemented in the GROMACS program was used to model the twelve fentanyl receptor agonists and the μ-opioid receptor protein compounds in water and to optimize the docking complex structure. Based on MM-PBSA methods, the APBS program was used to calculate the binding affinity of the complexes and the binding contant of receptor and liqand (Ki) values determined using MM-PBSA were consistent with the experimental values. Our predictions of compound activity sequences were, therefore, correct. The MD simulations of these complexes revealed that the protein structures in the complexes differed substantially from the structures of the ligand-free receptors. The backbone of the intracellular region segments IL2, IL3 and TM4 showed that the skeleton conformations had changed significantly. Different compounds may influence the receptor structure differently. Compounds with high activities may enhance binding flexibility in certain protein structural regions. These facts imply that fentanyl analogs may result in μ-opioid receptors changing to an active conformation after receptor binding. Physiologic effects may thus be triggered by a mediating signal transduction and by the activation of the G-protein.

Key words: Molecular dynamics, Fentanyl, μ-opioid receptor, Molecular docking

MSC2000: 

  • O643