Abstract

Coronavirus disease 2019 (COVID-19) is a pandemic viral disease caused by SARS-CoV-2 that generated serious damages for both the human population and the global economy. Therefore, it is currently considered as one of the most important global health problems of human societies and there is an urgent need for potent drugs or vaccines which can effectively combat this virus. The chymotrypsin-like protease (3CLpro) of SARS-CoV-2 plays a key role in the viral replication inside the host and thus is a promising drug target to design and develop effective antiviral drugs against SARS and other coronaviruses. This study evaluated some antiviral coumarin phytochemicals as potential inhibitors of coronaviruses 3CLpro by in silico approaches such as molecular docking, ADMET prediction, molecular dynamics simulation, and MM-PBSA binding energy calculation. Natural coumarin derivatives were docked to the 3CLpro of SARS-CoV-2 and for further investigation, docked to the 3CLpro of SARS-CoV and MERS-CoV. The docking scores of these natural compounds were compared with 3CLpro referenced inhibitors (ritonavir and lopinavir) and co-crystal inhibitor N3. Molecular docking studies suggested more than half of the coumarin phytochemicals had favorable interaction at the binding pocket of the coronaviruses 3CLpro and exhibited better binding affinities toward 3CLpro than ritonavir and lopinavir. Most antiviral phytochemicals interact strongly with one or both the catalytic dyad residues (His41 and Cys145) and the other key residues of SARS-CoV-2 main protease. Further, MD simulation and binding free energy calculations using MM-PBSA were carried out for three 3CLpro-coumarin complexes and 3CLpro-N3/lopinavir. The results confirmed that the 3CLpro-glycycoumarin, 3CLpro-oxypeucedanin hydrate, and 3CLpro-inophyllum P complexes were highly stable, experience fewer conformation fluctuations and share a similar degree of compactness. Also, the pharmacokinetics and drug-likeness studies showed good results for the selected coumarin phytochemicals.Therefore, the coumarin phytochemicals could be used as antiviral agents in the treatment of COVID-19 after further studies.

Graphical abstract

中文翻译：

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针对新型冠状病毒 SARS-CoV-2 的 3-糜蛋白酶样主蛋白酶的抗病毒香豆素衍生物的计算机分析和鉴定

摘要

2019 年冠状病毒病 (COVID-19) 是一种由 SARS-CoV-2 引起的大流行性病毒性疾病，对人类和全球经济都造成了严重损害。因此，它目前被认为是人类社会最重要的全球健康问题之一，迫切需要能够有效对抗这种病毒的强效药物或疫苗。SARS-CoV-2 的糜蛋白酶样蛋白酶 (3CLpro) 在宿主体内的病毒复制中起关键作用，因此是设计和开发针对 SARS 和其他冠状病毒的有效抗病毒药物的有希望的药物靶点。本研究通过分子对接、ADMET 预测、分子动力学模拟和 MM-PBSA 结合能计算等计算机方法评估了一些抗病毒香豆素植物化学物质作为冠状病毒 3CLpro 的潜在抑制剂。天然香豆素衍生物与 SARS-CoV-2 的 3CLpro 对接，为进一步研究，对接 SARS-CoV 和 MERS-CoV 的 3CLpro。将这些天然化合物的对接分数与 3CLpro 参考抑制剂（利托那韦和洛匹那韦）和共晶体抑制剂 N3 进行了比较。分子对接研究表明，超过一半的香豆素植物化学物质在冠状病毒 3CLpro 的结合口袋中具有良好的相互作用，并且对 3CLpro 的结合亲和力比利托那韦和洛匹那韦更好。大多数抗病毒植物化学物质与催化二元残基（His41 和 Cys145）和 SARS-CoV-2 主要蛋白酶的其他关键残基中的一个或两个发生强烈相互作用。此外，使用 MM-PBSA 对三种 3CLpro-香豆素复合物和 3CLpro-N3/洛匹那韦进行了 MD 模拟和结合自由能计算。结果证实，3CLpro-甘草香豆素、3CLpro-oxypeucedanin 水合物和 3CLpro-inophyllum P 复合物高度稳定，构象波动较少，并且具有相似的紧密度。此外，所选香豆素植物化学物质的药代动力学和药物相似性研究显示出良好的结果。因此，经过进一步研究，香豆素植物化学物质可用作治疗 COVID-19 的抗病毒剂。

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