Modeling the Structure-Activity Relationship of Arbidol Derivatives and Other SARS-CoV-2 Fusion Inhibitors Targeting the S2 Segment of the Spike Protein.
Modeling the Structure-Activity Relationship of Arbidol Derivatives and Other SARS-CoV-2 Fusion Inhibitors Targeting the S2 Segment of the Spike Protein.
复制标题
针对Spike蛋白S2片段的阿比多尔衍生物和其他SARS-CoV-2融合抑制剂的构效关系建模。
DOI：
10.1021/acs.jcim.1c01061
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发表时间：
2021-12-27
影响因子：
5.6
通讯作者：
Armen RS
中科院分区：
文献类型：
--
作者：
Freidel MR;Armen RS
据报道，Umifenovir（阿比朵尔）作为单药治疗COVID-19的多项临床试验显示出一定程度的疗效。它还显示出与其他直接作用的抗病毒药物如Remdesivir协同抑制SARS-CoV-2。使用计算方法来鉴定SARS-CoV-2刺突S2片段的最有利结合位点并进行虚拟筛选。在活SARS-CoV-2感染测定中评价从建模中选择的化合物。发现在C-4和C-6位置均具有取代的阿比朵尔（ARB）衍生物与ARB相比在活性和溶解度性质方面表现出适度的改善。然而，在基于病毒诱导的细胞病变效应的测定中，发现所有衍生物仅为部分抑制剂，而不是完全抑制剂。结合模式也证实了一系列的油酸三糖皂苷融合抑制剂的平行建模显示结合到S2段。最近确定的实验结构的刺突蛋白允许原子分辨率建模的融合抑制剂结合作为pH值的函数，直接作用的融合抑制剂靶向S2段的分子机制的影响进行了讨论。
Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such as Remdesivir. A computational approach was used to identify the most favorable binding site to the SARS-CoV-2 Spike S2 segment and to perform virtual screening. Compounds selected from modeling were evaluated in a live SARS-CoV-2 infection assay. An Arbidol (ARB) derivative with substitutions at both the C-4 and C-6 positions was found to exhibit a modest improvement in activity and solubility properties in comparison to ARB. However, all of the derivatives were found to only be partial inhibitors, rather than full inhibitors in a virus-induced cytopathic effect-based assay. The binding mode is also corroborated by parallel modeling of a series of oleanolic acid trisaccharide saponin fusion inhibitors shown to bind to the S2 segment. Recently determined experimental structures of the Spike protein allowed atomic resolution modeling of fusion inhibitor binding as a function of pH, and the implications for the molecular mechanism of direct-acting fusion inhibitors targeting the S2 segment are discussed.
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