Centre for Advanced Materials and Technologies, Warsaw University of Technology, Warsaw, Poland.
Applied Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland; Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Indonesia.
Methods. 2022 Jul;203:498-510. doi: 10.1016/j.ymeth.2022.02.004. Epub 2022 Feb 12.
For the last two years, the COVID-19 pandemic has continued to bring consternation on most of the world. According to recent WHO estimates, there have been more than 5.6 million deaths worldwide. The virus continues to evolve all over the world, thus requiring both vigilance and the necessity to find and develop a variety of therapeutic treatments, including the identification of specific antiviral drugs. Multiple studies have confirmed that SARS-CoV-2 utilizes its membrane-bound spike protein to recognize human angiotensin-converting enzyme 2 (ACE2). Thus, preventing spike-ACE2 interactions is a potentially viable strategy for COVID-19 treatment as it would block the virus from binding and entering into a host cell. This work aims to identify potential drugs using an in silico approach. Molecular docking was carried out on both approved drugs and substances previously tested in vivo. This step was followed by a more detailed analysis of selected ligands by molecular dynamics simulations to identify the best molecules that thwart the ability of the virus to interact with the ACE2 receptor. Because the SARS-CoV-2 virus evolves rapidly due to a plethora of immunocompromised hosts, the compounds were tested against five different known lineages. As a result, we could identify substances that work well on individual lineages and those showing broader efficacy. The most promising candidates among the currently used drugs were zafirlukast and simeprevir with an average binding affinity of -22 kcal/mol for spike proteins originating from various lineages. The first compound is a leukotriene receptor antagonist that is used to treat asthma, while the latter is a protease inhibitor used for hepatitis C treatment. From among the in vivo tested substances that concurrently exhibit promising free energy of binding and ADME parameters (indicating a possible oral administration) we selected the compound BDBM50136234. In conclusion, these molecules are worth exploring further by in vitro and in vivo studies against SARS-CoV-2.
在过去的两年里，COVID-19 大流行继续给世界大部分地区带来恐慌。根据世界卫生组织的最新估计，全球已有超过 560 万人死亡。该病毒在全球范围内继续进化，因此需要保持警惕，并找到和开发各种治疗方法，包括确定特定的抗病毒药物。多项研究证实，SARS-CoV-2 利用其膜结合的刺突蛋白识别人类血管紧张素转换酶 2（ACE2）。因此，阻止刺突-ACE2 相互作用是 COVID-19 治疗的一种潜在可行策略，因为它可以阻止病毒结合并进入宿主细胞。这项工作旨在使用计算方法确定潜在的药物。对已批准的药物和以前在体内测试过的物质进行了分子对接。然后，通过分子动力学模拟对选定的配体进行更详细的分析，以确定阻止病毒与 ACE2 受体相互作用的最佳分子。由于 SARS-CoV-2 病毒由于大量免疫功能低下的宿主而迅速进化，因此对五种不同的已知谱系进行了化合物测试。结果，我们可以确定对个别谱系有效且具有更广泛疗效的物质。在目前使用的药物中，最有前途的候选药物是扎鲁司特和西美瑞韦，它们对源自不同谱系的刺突蛋白的平均结合亲和力为-22 kcal/mol。第一种化合物是一种白三烯受体拮抗剂，用于治疗哮喘，而后者是一种用于丙型肝炎治疗的蛋白酶抑制剂。在具有有希望的结合自由能和 ADME 参数（表明可能口服给药）的同时在体内测试的物质中，我们选择了化合物 BDBM50136234。总之，这些分子值得进一步通过体外和体内研究来对抗 SARS-CoV-2。
