Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study
文献类型：期刊论文
| 作者 | Xu, Yechun ; Barrantes, Francisco J.; Shen, Jianhua; Luo, Xiaomin; Zhu, Weiliang; Chen, Kaixian; Jiang, Hualiang
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| 刊名 | JOURNAL OF PHYSICAL CHEMISTRY B
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| 出版日期 | 2006-10-19 |
| 卷号 | 110期号:41页码:20640-20648 |
| ISSN号 | 1520-6106 |
| DOI | 10.1021/jp0604591 |
| 文献子类 | Article |
| 英文摘要 | A large series of pharmacological agents, distinct from the typical competitive antagonists, block in a noncompetitive manner the permeability response of the nicotinic acetylcholine receptor ( nAChR) to the neurotransmitter acetylcholine. Taking the neuroleptic chlorpromazine (CPZ) as an example of such agents, the blocking mechanism of noncompetitive inhibitors to the ion channel pore of the nAChR has been explored at the atomic level using both conventional and steered molecular dynamics (MD) simulations. Repeated steered MD simulations have permitted calculation of the free energy (similar to 36 kJ/mol) of CPZ binding and identification of the optimal site in the region of the serine and leucine rings, at similar to 4 angstrom from the pore entrance. Coulomb and the Lennard-Jones interactions between CPZ and the ion channel as well as the conformational fluctuations of CPZ were examined to assess the contribution of each to the binding of CPZ to the nAChR. The MD simulations disclose a dynamic interaction of CPZ binding to the nAChR ionic channel. The cationic ammonium head of CPZ forms strong hydrogen bonds with Glu262 (alpha), Asp268 (beta), Glu272 (beta), Ser276 (beta), Glu280 (delta), Gln271 (gamma), Glu275 (gamma), and Asn279 (gamma) nAChR residues. Finally, the conventional MD simulation of CPZ at its identified binding site demonstrates that the binding of CPZ not only blocks ion transport through the channel but also markedly inhibits the |
| WOS关键词 | LIGAND-BINDING DOMAIN ; H-3 CHLORPROMAZINE ; EXTRACELLULAR DOMAIN ; GATING MECHANISM ; PROTEIN ; MODEL ; BLOCKERS ; SITES ; BILAYER ; SUBUNIT |
| 资助项目 | NIDA NIH HHS[1 R01 DA015389] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000241192200082 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273468]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Hualiang |
| 作者单位 | 1.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res,Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Grad Sch, Shanghai 201203, Peoples R China 4.Inst Invest Bioquim Bahia Blanca, Bahia Blanca, Argentina 5.UNESCO, Chair Biophys & Mol Neurobiol, Bahia Blanca, Argentina |
| 推荐引用方式 GB/T 7714 | Xu, Yechun,Barrantes, Francisco J.,Shen, Jianhua,et al. Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2006,110(41):20640-20648. |
| APA | Xu, Yechun.,Barrantes, Francisco J..,Shen, Jianhua.,Luo, Xiaomin.,Zhu, Weiliang.,...&Jiang, Hualiang.(2006).Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.JOURNAL OF PHYSICAL CHEMISTRY B,110(41),20640-20648. |
| MLA | Xu, Yechun,et al."Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study".JOURNAL OF PHYSICAL CHEMISTRY B 110.41(2006):20640-20648. |
入库方式： OAI收割
来源：上海药物研究所
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