| Pharmacophore-directed Homology Modeling and Molecular Dynamics Simulation of G Protein-coupled Receptor： Study of Possible Binding Modes of 5-HT2c Receptor Agonists |
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| 引用本文： | Zuo Z,Chen G,Luo X,Puah C,Zhu W,Chen K,Jiang H. Pharmacophore-directed Homology Modeling and Molecular Dynamics Simulation of G Protein-coupled Receptor： Study of Possible Binding Modes of 5-HT2c Receptor Agonists[J]. Acta biochimica et biophysica Sinica, 2007, 39(6): 413-422 |
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| 作者姓名： | Zuo Z Chen G Luo X Puah C Zhu W Chen K Jiang H |
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| 作者单位： | Centre for |
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| 基金项目： | This work was supported by the grants from Shanghai Key R＆D Program （No. 036505003）, the National Key R＆D Program （2005BA711A04）, and the Major State Basic Research Development Program of China （2004CB518901） |
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| 摘 要： | A new pharmacophore-based modeling procedure, including homology modeling, pharmacophore study, flexible molecular docking, and long-time molecular dynamics (MD) simulations, was employed to construct the structure of the human 5-HT_(2C) receptor and determine the characteristics of binding modes of 5-HT_(2C) receptor agonists. An agonist-receptor complex has been constructed based on homology modeling and a pharmacophore hypothesis model based on some high active compounds. Then MD simulations of the ligand-receptor complex in an explicit membrane environment were carried out. The conformation of the 5- HT_(2C) receptor during MD simulation was explored, and the stable binding modes of the studied agonist were determined. Flexible molecular docking of several structurally diverse agonists of the human 5-HT_(2C) receptor was carried out, and the general binding modes of these agonists were investigated. According to the models presented in this work and the results of Flexi-Dock, the involvement of the amino acid residues Asp134, Ser138, Ash210, Asn331, Tyr358, Ile131, Ser132, Val135, Thr139, Ile189, Val202, Val208, Leu209, Phe214, Val215, Gly218, Ser219, Phe223, Trp324, Phe327, and Phe328 in agonist recognition was studied. The obtained binding modes of the human 5-HT_(2C) receptor agonists have good agreement with the site-directed mutagenesis data and other studies.
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| 关 键 词： | 药效团 蛋白 分子机制 同源模型 |
| 修稿时间： | 2007-02-052007-03-15 |
Pharmacophore-directed homology modeling and molecular dynamics simulation of G protein-coupled receptor: study of possible binding modes of 5-HT2C receptor agonists |
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| Zuo Zhili,Chen Gang,Luo Xiaomin,Puah Chummok,Zhu Weiliang,Chen Kaixian,Jiang Hualiang. Pharmacophore-directed homology modeling and molecular dynamics simulation of G protein-coupled receptor: study of possible binding modes of 5-HT2C receptor agonists[J]. Acta biochimica et biophysica Sinica, 2007, 39(6): 413-422 |
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| Authors: | Zuo Zhili Chen Gang Luo Xiaomin Puah Chummok Zhu Weiliang Chen Kaixian Jiang Hualiang |
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| Affiliation: | Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. |
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| Abstract: | A new pharmacophore-based modeling procedure, including homology modeling, pharmacophore study, flexible molecular docking, and long-time molecular dynamics (MD) simulations, was employed to construct the structure of the human 5-HT_(2C) receptor and determine the characteristics of binding modes of 5-HT_(2C) receptor agonists. An agonist-receptor complex has been constructed based on homology modeling and a pharmacophore hypothesis model based on some high active compounds. Then MD simulations of the ligand-receptor complex in an explicit membrane environment were carried out. The conformation of the 5- HT_(2C) receptor during MD simulation was explored, and the stable binding modes of the studied agonist were determined. Flexible molecular docking of several structurally diverse agonists of the human 5-HT_(2C) receptor was carried out, and the general binding modes of these agonists were investigated. According to the models presented in this work and the results of Flexi-Dock, the involvement of the amino acid residues Asp134, Ser138, Ash210, Asn331, Tyr358, Ile131, Ser132, Val135, Thr139, Ile189, Val202, Val208, Leu209, Phe214, Val215, Gly218, Ser219, Phe223, Trp324, Phe327, and Phe328 in agonist recognition was studied. The obtained binding modes of the human 5-HT_(2C) receptor agonists have good agreement with the site-directed mutagenesis data and other studies. |
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| Keywords: | 5-HT_(2C) receptor Flexi-Dock G protein-coupled receptor homology modeling molecular dynamics simulation |
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