Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study

doi:10.1021/jp0604591

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	Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study
	Xu, Yechun; Barrantes, Francisco J.; Shen, Jianhua; Luo, Xiaomin; Zhu, Weiliang; Chen, Kaixian; Jiang, Hualiang
刊名	JOURNAL OF PHYSICAL CHEMISTRY B
	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
资助项目	NIDA NIH HHS[1 R01 DA015389]
WOS关键词	LIGAND-BINDING DOMAIN ; H-3 CHLORPROMAZINE ; EXTRACELLULAR DOMAIN ; GATING MECHANISM ; PROTEIN ; MODEL ; BLOCKERS ; SITES ; BILAYER ; SUBUNIT
WOS研究方向	Chemistry
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000241192200082
内容类型	期刊论文
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.