How amantadine and rimantadine inhibit proton transport in the M2 protein channel

被引:64
作者
Intharathep, Pathumwadee [1 ]
Laohpongspaisan, Chittima [1 ]
Rungrotmongkol, Thanyada [1 ]
Loisruangsin, Arthorn [2 ]
Malaisree, Maturos [1 ]
Decha, Panita [1 ]
Aruksakunwong, Ornjira [3 ]
Chuenpennit, Krit [1 ]
Kaiyawet, Nopphorn [1 ]
Sompornpisut, Pornthep [1 ]
Pianwanit, Somsak [1 ]
Hannongbua, Supot [1 ]
机构
[1] Chulalongkorn Univ, Fac Sci, Dept Chem, Bangkok 10330, Thailand
[2] Kasetsart Univ Kamphaeng Saen Campus, Fac Liberal Arts & Sci, Nakhon Pathom 73140, Thailand
[3] Rangsit Univ, Fac Sci, Dept Chem, Pathum Thani 12000, Thailand
关键词
Influenza A; M2; channel; Amantadine; Rimantadine; Molecular dynamics simulations;
D O I
10.1016/j.jmgm.2008.06.002
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:342 / 348
页数:7
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