How amantadine and rimantadine inhibit proton transport in the M2 protein channel
How amantadine and rimantadine inhibit proton transport in the M2 protein channel
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DOI：
10.1016/j.jmgm.2008.06.002
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发表时间：
2008-10-01
影响因子：
2.9
通讯作者：
Hannongbua, Supot
中科院分区：
文献类型：
--
作者：
Intharathep, Pathumwadee;Laohpongspaisan, Chittima;Hannongbua, Supot
为了了解抗病毒药物如何通过M2离子通道抑制甲型流感病毒的复制，分子动力学模拟已应用于游离形式的M2离子通道及其与完全水合脂质双层中的两种商业药物的复合物的六种可能的质子化状态。在六种不同状态的游离M2四聚体中，单质子化、邻位双质子化、三质子化和四质子化体系的孔隙中均存在水密度。在抑制剂的存在下，金刚乙胺比金刚烷胺更好地降低通道中的水密度，与实验IC 50值一致。利用两种药物在所有状态下的优先位置和取向，清楚地解释了药物结合到开放孔和组氨酸门的两种作用机制，即，(i)抑制剂被检测到本地化稍微接近组氨酸门，可以促进His37咪唑环的方向在于在封闭的构象和（ii）抑制剂作为一个阻滞剂，结合在几乎以上的开放孔，并与三个孔内衬残基，Leu26，Ala3O和Ser31轻微的相互作用。在这里，发现抑制剂由于它们的变构阻碍而与通道非常弱地结合，而它们的侧链被强烈溶剂化。(C)2008年爱思唯尔公司All rights reserved.
To understand how antiviral drugs inhibit the replication of influenza A virus via the M2 ion channel, molecular dynamics simulations have been applied to the six possible protonation states of the M2 ion channel in free form and its complexes with two commercial drugs in a fully hydrated lipid, bilayer. Among the six different states of free M2 tetramer, water density was present in the pore of the systems with mono-protonated, di-protonated at adjacent position, tri-protonated and tetra-protonated systems. In the presence of inhibitor, water density in the channel was considerably better reduced by rimantadine than amantadine, agreed well with the experimental IC50 values. With the preferential position and orientation of the two drugs in all states, two mechanisms of action, where the drug binds to the opening pore and the histidine gate, were clearly explained, i.e., (i) inhibitor was detected to localize slightly closer to the histidine gate and can facilitate the orientation of His37 imidazole rings to lie in the close conformation and (ii) inhibitor acts as a blocker, binding at almost above the opening pore and interacts slightly with the three pore-lining residues, Leu26, AIa3O and Ser31. Here, the inhibitors were found to bind very weakly to the channel due to their allosteric hindrance while theirs side chains were strongly solvated. (C) 2008 Elsevier Inc. All rights reserved.