Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.
Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.
复制标题
非竞争性抑制剂氯丙嗪阻断烟碱乙酰胆碱受体离子通道：分子动力学模拟研究。
DOI：
10.1021/jp0604591
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Jiang,Hualiang
中科院分区：
文献类型：
--
作者：
Xu,Yechun;Barrantes,FranciscoJ;Shen,Jianhua;Luo,Xiaomin;Zhu,Weiliang;Chen,Kaixian;Jiang,Hualiang
与典型的竞争性拮抗剂不同，许多药物以非竞争性的方式阻断烟碱型乙酰胆碱受体(NAChR)对神经递质乙酰胆碱的通透性反应。以抗精神病药氯丙嗪(CPZ)为例，从原子水平探讨了非竞争性抑制剂对nAChR离子通道孔的封闭机理。重复的定向分子动力学模拟计算了CPZ结合的自由能(∼36kJ/摩尔)，并确定了丝氨酸环和亮氨酸环区域的最佳位置，该位置位于从孔入口处的∼4？处。考察了CPZ与离子通道的库仑相互作用和Lennard-Jones相互作用以及CPZ的构象波动，以评估它们对CPZ与nAChR结合的贡献。分子动力学模拟揭示了CPZ与nAChR离子通道的动态相互作用。CPZ的阳离子氨头与Glu262(α)、Asp268(β)、Glu272(β)、Ser276(β)、Glu280(δ)、Gln271(γ)、Glu275(γ)和Asn279(γ)nAChR残基形成强氢键。最后，CPZ在其已识别的结合部位的常规MD模拟表明，CPZ的结合不仅阻止了离子通过通道的运输，而且显著地抑制了通道的构象转变，这是nAChR发挥其生物学功能所必需的。
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 (∼36 kJ/mol) of CPZ binding and identification of the optimal site in the region of the serine and leucine rings, at ∼4 Å 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 (α), Asp268 (β), Glu272 (β), Ser276 (β), Glu280 (δ), Gln271 (γ), Glu275 (γ), and Asn279 (γ) 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 conformational transitions of the channel, necessary for nAChR to carry out its biological function.