Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeyskaya St., Samara, Samara Region, 443100, Russia.
Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeyskaya St., Samara, Samara Region, 443100, Russia.
Eur J Med Chem. 2021 Oct 5;221:113485. doi: 10.1016/j.ejmech.2021.113485. Epub 2021 Apr 29.
Currently, smallpox, caused by the variola virus belonging to the poxvirus family, has been completely eradicated according to the WHO. However, other representatives of poxviruses, such as vaccinia virus, cowpox virus, ectromelia virus, monkeypox virus, mousepox virus and others, remain in the natural environment and can infect both animals and humans. The pathogens of animal diseases, belonging to the category with a high epidemic risk, have already caused several outbreaks among humans, and can, in an unfavorable combination of circumstances, cause not only an epidemic, but also a pandemic. Despite the fact that there are protocols for the treatment of poxvirus infections, the targeted design of new drugs will increase their availability and expand the arsenal of antiviral chemotherapeutic agents. One of the potential targets of poxviruses is the p37 protein, which is a tecovirimat target. This protein is relatively small, has no homologs among proteins of humans and other mammals and is necessary for the replication of viral particles, which makes it attractive target for virtual screening. Using the I-TASSER modelling and molecular dynamics refinement the p37 orthopox virus protein model was obtained and its was confirmed by ramachandran plot analysis and superimposition of the model with the template protein with similar function. A virtual library of adamantane containing compounds was generated and a number of potential inhibitors were chosen from virtual library using molecular docking. Several compounds bearing adamantane moiety were synthesized and their biological activity was tested in vitro on vaccinia, cowpox and mousepox viruses. The new compounds inhibiting vaccinia virus replication with IC concentrations between 0.133 and 0.515 μM were found as a result of the research. The applied approach can be useful in the search of new inhibitors of orthopox reproduction. The proposed approach may be suitable for the design of new poxvirus inhibitors containing cage structural moiety.
目前，根据世界卫生组织的说法，天花已被完全根除，天花是由痘病毒家族的天花病毒引起的。然而，其他痘病毒，如牛痘病毒、牛痘病毒、猴痘病毒、鼠痘病毒等，仍存在于自然环境中，既能感染动物也能感染人类。动物疾病的病原体，属于高流行风险类别，已经在人类中引起了几次爆发，并且在不利的环境条件下，不仅会引起流行，还会引起大流行。尽管有治疗痘病毒感染的方案，但新药物的靶向设计将增加它们的可用性，并扩大抗病毒化学治疗剂的储备。痘病毒的一个潜在靶点是 p37 蛋白，这是特考韦瑞的靶点。这种蛋白质相对较小，在人类和其他哺乳动物的蛋白质中没有同源物，是病毒颗粒复制所必需的，这使其成为虚拟筛选的有吸引力的目标。使用 I-TASSER 建模和分子动力学细化，获得了 p37 正痘病毒蛋白模型，并通过拉马钱德兰图谱分析和与具有相似功能的模板蛋白的模型叠加来证实。生成了含有金刚烷的虚拟化合物库，并使用分子对接从虚拟库中选择了一些潜在的抑制剂。合成了几种带有金刚烷部分的化合物，并在体外对牛痘、牛痘和鼠痘病毒进行了生物活性测试。研究发现，几种具有金刚烷部分的化合物能抑制牛痘病毒的复制，IC浓度在 0.133 和 0.515 μM 之间。研究结果表明，该方法可用于寻找新的正痘病毒抑制剂。所提出的方法可能适合设计含有笼状结构部分的新痘病毒抑制剂。
