κ阿片受体与拮抗剂作用机制的计算机模拟研究  

Molecular Simulation of κ Opioid Receptor and Antagonist Interaction Mechanism

作　　者：丁俊杰[1] 丁晓琴[1] 

机构地区：[1]北京药物化学研究所,北京102205

出　　处：《中国药学杂志》2011年第10期747-752,共6页Chinese Pharmaceutical Journal

摘　　要：目的构建人κ阿片受体三维结构模型,探讨拮抗剂与受体作用机制。方法应用同源模建方法构建人κ阿片受体三维结构模型,采用Profile-3D和Ram achandran图验证模型的可靠性。将选择性κ阿片受体拮抗剂5-′GNTI与受体进行分子对接和分子动力学优化,得到拮抗状态κ阿片受体模型。采用AutoDock对接软件将受体与测试集拮抗剂进行分子对接研究。结果搜寻和分析受体的活性位点,确定合理的κ阿片受体结合口袋。训练集和测试集化合物与受体对接的结合自由能ΔG和实际活性lgKi之间具有较好的相关性,相关系数为0.779,各类拮抗剂与受体结合的关键氨基酸残基与实验结果基本一致。说明本研究构建的拮抗状态受体模型比较合理。结论建立了合理的κ阿片受体模型和拮抗状态受体模型,探讨各类拮抗剂与κ阿片受体的作用机制,为设计新型选择性κ阿片受体拮抗剂奠定理论基础。OBJECTIVE To build the three-dimensional model of human κ opioid receptor and study its interaction mechanism with antagonist.METHODS The three-dimensional model of κ opioid receptor was built through homology modeling,while the reliability of the model was assessed by Profile-3D analysis and Ramachandran plot.The active site of human κ opioid receptor was searched by DS/Define and Edit Binding Site,and the reasonable active cavity was gained.Then the selective antagonist 5′-GNTI was docked into κ opioid receptor model using CDOCKER.A series of molecular mechanics and dynamics operations were performed to find the most stable binding interaction between 5′-GNTI and the receptor.The ＂antagonist-bound＂ receptor model was built and test set antagonists were docked using AutoDock program.RESULTS There was a good linear relationship between ΔG and the experimental affinity lgKi（correlation r=0.779）.The ionic interaction was formed between the Asp138 residue at TMⅢ and the protonated amine of different antagonist classes,while the Tyr 139 at TMⅢ,Phe231 and Phe235 at TMV,and Trp287 and His291 at TMVI interacted with the hydrophobic groups or aromatic groups of antagonists with hydrophobic or π-π interaction.CONCLUSION The built receptor model is reasonable and may be used in designing new more active and selective antagonsits.The present study provides a consistent framework for further investigation of the opioid receptor-ligand interaction mechanisms.

关 键 词：阿片受体 同源模建 拮抗剂 分子对接 

分 类 号：O641[理学—物理化学] I914[理学—化学]