Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, 901 Walnut St. Suite 918, Philadelphia, Pennsylvania 19170, United States.
J Chem Inf Model. 2021 Dec 27;61(12):5906-5922. doi: 10.1021/acs.jcim.1c01061. Epub 2021 Dec 13.
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.
乌米酚（阿比多尔）在多项 COVID-19 单药治疗的临床试验中显示出一定程度的疗效。它还与瑞德西韦等其他直接作用抗病毒药物表现出协同抑制 SARS-CoV-2 的作用。本研究采用计算方法来确定与 SARS-CoV-2 刺突 S2 片段结合的最有利的结合位点，并进行虚拟筛选。从建模中选择的化合物在活 SARS-CoV-2 感染测定中进行了评估。与 ARB 相比，在 C-4 和 C-6 位取代的阿比多尔（ARB）衍生物在活性和溶解度性质方面表现出适度改善。然而，所有衍生物在基于病毒诱导的细胞病变效应的测定中都被发现只是部分抑制剂，而不是完全抑制剂。结合模式也通过平行建模一系列与 S2 段结合的齐墩果酸三糖皂苷融合抑制剂得到证实。最近确定的 Spike 蛋白实验结构允许在 pH 作为函数的情况下对融合抑制剂结合进行原子分辨率建模，并讨论了针对 S2 段的直接作用融合抑制剂的分子机制的影响。
