嗅觉受体的分子模拟及其在中药五味研究中的应用

【作者】 徐阳；

【导师】 刘培勋； 李松年； 龙伟；

【作者基本信息】 中国协和医科大学 ， 药物化学， 2010， 硕士

【摘要】 如今各种生化药理机制已经进入分子微观的阐释阶段,而中药作为一种历史悠久,疗效显著的传统医药,其药性理论、作用机理都不甚明确。本课题利用分子模拟虚拟实验直接触及分子微观世界的形象表达,借助计算机对微观分子进行操作,揭示中药药性理论中辛味药的微观分子作用机理,为中药中辛味药治疗作用提供理论依据和支持。在计算机平台上利用同源模建的方法模拟嗅觉受体,开展对嗅觉受体三维结构的模建与分析,进行分子动力学研究,找到嗅觉受体活性位点与关键残基,探索辛味中药发挥作用的真正原因,这些都具有分子药理学意义,而利用这些信息将为新型抗肿瘤药物的开发积累经验并探索道路。本文利用同源模建、分子力学优化和分子动力学模拟等方法对三种嗅觉受体蛋白进行了三维结构预测并与辛味中药进行分子对接的研究,从而揭示中药药性理论中辛味药的微观作用机理,为中药中辛味药治疗疾病提供理论依据和支持。主要结果如下：1.通过同源模建和分子动力学模拟,得到了OR7D4,OR1D2,OR51E1的活性构象和OR1D2的抑制构象2.通过分子对接以及结果的分析,得到了辛味中药的物质基础,辛味中药作用的第一个环节可能是嗅觉受体,激活嗅觉受体,引起一系列的下游反应。更多还原

【Abstract】 Nowaday, various of pharmacological and biochemical mechanisms have been explaned at the molecule level, while traditional Chinese medicine with a long history and significant effect, its medicinal theory and mechanism are unclear. This course will use molecular modeling experiments which directly express the virtual image of the microscopic world to reveal the micro-molecular mechanism of pungent Chinese herbal medicine, and provide a theoretical basis and support for the theory of the therapeutic effect of pungent Chinese medicine. Using homology modeling approach to carry out three-dimensional structure of the olfactory receptor modeling and analysis, Using molecular dynamics to find key active site residues of olfactory receptor, Using docking technique to explore the interaction between pungent Chinese herbal medicine and olfactory receptors, these provid the information and thoughts for the finding and developing new anticancer drugs,and privod theoretical support for relacted experience.In this paper, The three-dimensional structure of three typical olfactory receptors were predicted using homology modeling, molecular mechanics and molecular dynamics simulation optimization methods. The relation between pungent Chinese herbal medicine and olfactory receptors has been researched with molecular docking method, which reveals the mechanisms of pungent Chinese herbal medicine action. This study provides a theoretical basis and support for the theory of the role of micro-mechanism for the Chinese medicine.The main results are as follows:1. The active conformations of OR7D4,OR1D2, OR51E1 and the conformation of inhibitory OR1D2 have been simulated using homology modeling and molecular dynamics simulations.2. The results of molecular docking between olfactory receptor and pungent Chinese herbal medicine were analysised,which reveals material basis of pungent Chinese medicine, It’s inferred that the first step for pungent traditional Chinese medicine activate olfactory receptors,and then cause a series of downstream reactions.更多还原