Rimantadine Binds to and Inhibits the Influenza A M2 Proton Channel without Enantiomeric Specificity.
Rimantadine Binds to and Inhibits the Influenza A M2 Proton Channel without Enantiomeric Specificity.
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DOI：
10.1021/acs.biochem.1c00437
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发表时间：
2021-08-03
期刊：
影响因子：
2.9
通讯作者：
Kolocouris A
中科院分区：
文献类型：
--
作者：
Thomaston JL;Samways ML;Konstantinidi A;Ma C;Hu Y;Bruce Macdonald HE;Wang J;Essex JW;DeGrado WF;Kolocouris A
甲型流感M2野生型(WT)质子通道是抗流感药物金刚乙胺的靶点。金刚乙胺有两个对映体，尽管大多数关于药物结合和抑制的研究都使用了外消旋混合物。使用全长-M2 WT的固态核磁共振实验显示了显著的光谱差异，这被解释为(R)-vs(S)-金刚乙胺的结合更加紧密。然而，尚不清楚这是否与药物结合和抑制方面的功能差异有关。用X-射线结晶学方法测定了(R)-和(S)-金刚乙胺都结合在M2的WT孔上，但水合作用略有不同。然而，这并不会导致效力或结合动力学上的差异，如电生理检测中的Kon、Koff和Kd的相似值以及细胞检测中的EC50值所示。我们的结论是，(R)-和(S)-金刚乙胺对映体水合作用的微小差异与药物结合或通道抑制无关。为了进一步探讨M2孔的水化对结合亲和力的影响，用巨正则系综分子动力学模拟计算了水的结构随水的化学势的变化。最初，结合药物和通道门控His37残基之间的两层有序水分子掩盖了药物的手性。随着化学势变得更加不利，药物向下转移到较低的水层，相互作用对手性变得更加敏感。这些研究表明，在新药中取代上层水层并具体识别下层水层是可行的。
The influenza A M2 wild-type (WT) proton channel is the target of the anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into drug binding and inhibition have used a racemic mixture. Solid-state NMR experiments using the full length-M2 WT have shown significant spectral differences that were interpreted to indicate tighter binding for (R)- vs (S)-rimantadine. However, it was unclear if this correlates with a functional difference in drug binding and inhibition. Using X-ray crystallography, we have determined that both (R)- and (S)-rimantadine bind to the M2 WT pore with slight differences in the hydration of each enantiomer. However, this does not result in a difference in potency or binding kinetics, as shown by similar values for kon, koff, and Kd in electrophysiological assays and for EC50 values in cellular assays. We concluded that the slight differences in hydration for the (R)- and (S)-rimantadine enantiomers are not relevant to drug binding or channel inhibition. To further explore the effect of the hydration of the M2 pore on binding affinity, the water structure was evaluated by grand canonical ensemble molecular dynamics simulations as a function of the chemical potential of the water. Initially, the two layers of ordered water molecules between the bound drug and the channel’s gating His37 residues mask the drug’s chirality. As the chemical potential becomes more unfavorable, the drug translocates down to the lower water layer, and the interaction becomes more sensitive to chirality. These studies suggest the feasibility of displacing the upper water layer and specifically recognizing the lower water layers in novel drugs.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
7.3
作者：
Duque MD;Ma C;Torres E;Wang J;Naesens L;Juárez-Jiménez J;Camps P;Luque FJ;DeGrado WF;Lamb RA;Pinto LH;Vázquez S
通讯作者：
Vázquez S
影响因子：
4.2
作者：
Drakopoulos, Antonios;Tzitzoglaki, Christina;Kolocouris, Antonios
通讯作者：
Kolocouris, Antonios
影响因子：
3.7
作者：
Dong G;Peng C;Luo J;Wang C;Han L;Wu B;Ji G;He H
通讯作者：
He H
影响因子：
2.9
作者：
Andreas, Loren B.;Barnes, Alexander B.;Griffin, Robert G.
通讯作者：
Griffin, Robert G.