嗅觉受体的分子模拟及其在中药五味研究中的应用
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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。
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.
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。
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.
引文
1高学敏中药学[M]中国中医药出版社2002.9
2刘时觉试论辛味[J]浙江中医学院学报2004,9,28,(5)8-10
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14 Krautwurst D. Human olfactory receptor families and their odorants[J] Chem Biodivers 2008,5:842-852
1叶德泳 计算机辅助药物设计导论[M]化学工业出版社2004.1
2徐筱杰 侯廷军 乔学斌 章威 计算机辅助药物分子设计[M]北京：化工出版社2007,150—162
3陈凯先 蒋华良 嵇汝运 计算机辅助药物设计——原理、方法及应用[M]上海：上海科学出版社2000：417-421
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1.高学敏 中药学 中国中医药出版社 2002.9
2.http://202.127.145.134/scdb
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3.Al-Lazikani B.,Jung J.,Xiang Z. X.,et al. Protein structure prediction [J],.Curr.Opin.i n Chem.Biol 2001,5:51-56
4.BakerD.,Sali A.. Protein structure prediction and structural genomics [J],Science. 2001,294(5540):93-96
5.Ginalski K..Gfishin N.V.,Godzik A.,et al Practical lessons from protein structure prediction. [J]Nucleic Acid Res.,2005,33(6):1874-1891
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9 Brian K. Kobilka. G protein coupled receptor structure and activation [J] Biochimica et Biophysica Acta 2007,1768(4):794-807
10 Matthew N. Davies et al. Proteomic applications of automated GPCR classification[J] Proteomics.2007,7(16):2800-14
11 Sadashiva S. Karnik, et al. Activation of G-protein-coupled receptors:a common molecular mechanism[J] TRENDS in Endocrinology and Metabolism 2003,14(9):431-6
12 Sadashiva S. K. et al. Activation of G-protein-coupled receptors:a common molecular mechanism[J] Trends Endocrinol Metab.2003,14:431-437
13 Z. Zou; Buck L. B. Combinatorial effects of odorant mixes in olfactory cortex[J] Science 2006,311:1477-1485
14 Krautwurst D. Human olfactory receptor families and their odorants[J] Chem Biodivers 2008,5:842-852
1叶德泳 计算机辅助药物设计导论[M]化学工业出版社2004.1
2徐筱杰 侯廷军 乔学斌 章威 计算机辅助药物分子设计[M]北京：化工出版社2007,150—162
3陈凯先 蒋华良 嵇汝运 计算机辅助药物设计——原理、方法及应用[M]上海：上海科学出版社2000：417-421
4. Von Itzstein M, Wu W Y et al. Rational design of potent sialidase-based inhibitors of influenza virus replication[J]. Nature,1993,363:418-423
5.来鲁华等,蛋白质的结构预测与分子设计[M],北京大学出版社,1993。
6. Skouloubris S, Labihne A, Reuse HD. The AmiE aliphatic amidase and AmiF formamidase of Helicobacter pylori:natural evolution of two enzyme paralogues [J]Mol. Micro.2001,40:596-609.
7. Greer J. Model structure for the inflammatory protein C5a[J] Science.1985, 228:1055-1060.
8. Blundell TL, Sibanda BL, Sternberg MJE, Thornton JM. Knowledge-based prediction of protein structures and the design of novel molecules[J] Nature,1987. 326:347-362
9 D. E. Koshland. Application of a Theory of Enzyme Specificity to Protein Synthesis[J]. Proc.Natl. Acad. Sci. USA.1958,44:98-104
10. F. Jiang, S. H. Kim, "Soft docking"; matching of molecular surface cubes[J]. J Mol Biol,1991,219:79-102.
11.I. D. Kuntz, Structure-Based Strategies for Drug Design and Discovery[J] Science, 1992,257:1078-1082.
12. D. S. Goodsell, A. J. Olson, Automated Docking of Substrates to Proteins by Simulated Annealing[J].Proteins,1990,8:195-202.
13. I. D. Kuntz, Structure-based strategies for drug design and discovery[J].Science, 1992,257,1078-1082.
14.Duan, Y. Kollman, P. A. Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. [J].Science,1998,282,740-744.
15.Zhong, Q. Jiang, Q. Moore, P. B. Newns, D. M. Klein, M. L. Molecular dynamics simulation of a synthetic ion channel[J].Biophys. J.,1998,74,3.
16.Zhong, Q. Moore, P. B. Newns, D. M. Klein, M. L. Molecular dynamics study of the LS3 voltage-gated ion channel[J]. FEBS Lett,1998,427,267-274.
1.高学敏 中药学 中国中医药出版社 2002.9
2.http://202.127.145.134/scdb
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