当前位置：
X-MOL 学术
›
ACS Med. Chem. Lett.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-29 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00458 Antonios Drakopoulos 1 , Christina Tzitzoglaki 1 , Kelly McGuire 2 , Anja Hoffmann 3 , Athina Konstantinidi 1 , Dimitrios Kolokouris 1 , Chunlong Ma 4 , Kathrin Freudenberger 5 , Johanna Hutterer 5 , Günter Gauglitz 5 , Jun Wang 4 , Michaela Schmidtke 3 , David D. Busath 2 , Antonios Kolocouris 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-29 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00458 Antonios Drakopoulos 1 , Christina Tzitzoglaki 1 , Kelly McGuire 2 , Anja Hoffmann 3 , Athina Konstantinidi 1 , Dimitrios Kolokouris 1 , Chunlong Ma 4 , Kathrin Freudenberger 5 , Johanna Hutterer 5 , Günter Gauglitz 5 , Jun Wang 4 , Michaela Schmidtke 3 , David D. Busath 2 , Antonios Kolocouris 1
Affiliation
|
Recently, the binding kinetics of a ligand–target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
中文翻译：
阐明金刚烷胺变体对M2 WT和S31N流感病毒的结合，质子阻断和抑制作用
最近，配体与靶标相互作用的结合动力学，例如小分子在其蛋白靶标上的停留时间，被认为对药物疗效越来越重要。在这里，我们调查这些概念，以解释带有逐渐增大的烷基的金刚乙胺变体对甲型流感病毒M2野生型（WT）和M2 S31N蛋白质子通道的结合和质子封闭。我们显示，与M2 WT相比，M2 S31N对金刚烷胺类似物的抗药性是由于其k off率高于k on速率根据电生理学（EP）测量。这是由于以下事实：在M2 S31N中，金刚烷基笼的V27凹腔的丢失导致M2孔内部的停留时间很短。两种金刚烷胺对映体均具有相似的通道阻滞，并且与M2 WT的k on和k off结合。为了比较金刚乙胺变体与M2的效价，我们采用了M2的不同模拟方法，即等温滴定量热法和分子动力学模拟，EP和抗病毒测定。还显示出，M2 WT位点28处氨基酸的微小变化（不排在孔中）严重影响了M2 WT的阻断动力学。
更新日期：2018-01-29
中文翻译：
阐明金刚烷胺变体对M2 WT和S31N流感病毒的结合，质子阻断和抑制作用
最近，配体与靶标相互作用的结合动力学，例如小分子在其蛋白靶标上的停留时间，被认为对药物疗效越来越重要。在这里，我们调查这些概念，以解释带有逐渐增大的烷基的金刚乙胺变体对甲型流感病毒M2野生型（WT）和M2 S31N蛋白质子通道的结合和质子封闭。我们显示，与M2 WT相比，M2 S31N对金刚烷胺类似物的抗药性是由于其k off率高于k on速率根据电生理学（EP）测量。这是由于以下事实：在M2 S31N中，金刚烷基笼的V27凹腔的丢失导致M2孔内部的停留时间很短。两种金刚烷胺对映体均具有相似的通道阻滞，并且与M2 WT的k on和k off结合。为了比较金刚乙胺变体与M2的效价，我们采用了M2的不同模拟方法，即等温滴定量热法和分子动力学模拟，EP和抗病毒测定。还显示出，M2 WT位点28处氨基酸的微小变化（不排在孔中）严重影响了M2 WT的阻断动力学。
京公网安备 11010802027423号