The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1^st, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2.

截至4月1^日，新型冠状病毒（SARS-CoV-2）已感染超过850,000人，并在全球造成42,000多人死亡。2020年。由于该疾病在世界范围内迅速传播，因此迫切需要找到有效的药物来治疗该病毒。SARS-CoV-2的主要蛋白酶（Mpro）是潜在的药物靶标之一。在这项工作中，我们使用了严格的计算方法，包括分子对接，配体的快速拉动（FPL）和自由能扰动（FEP），来研究SARS-CoV-2 Mpro的潜在抑制剂。我们首先用三种报告的SARS-CoV-2 Mpro抑制剂测试了我们的方法。并且我们的计算结果与相应的实验数据非常吻合。随后，我们在越南植物中发现的约4600种天然化合物以及8种可利用的HIV-1蛋白酶（PR）抑制剂和氮杂肽环氧化物的数据库中应用了我们的方法。分子对接产生了35种天然化合物的简短列表，随后使用FPL方案对其进行了完善。FPL模拟产生了五种潜在的抑制剂，包括3种天然化合物和两种可用的HIV-1 PR抑制剂。最后，最准确，最精确的方法FEP用于确定这五种化合物的绝对结合自由能。FEP结果表明，两种天然化合物cannabisin A和异类叶升麻苷，和HIV-1 PR抑制剂，地瑞那韦，表现出大的结合自由能，以SARS-CoV的-2 MPRO，其比大13b中，近期报道的最可靠的SARS-CoV的-2 MPRO抑制剂。结合自由能主要来自范德华（vdW）相互作用。我们还发现，Glu166与所有抑制剂形成氢键。用丙氨酸残基替代Glu166会导致darunavir对SARS-CoV-2 Mpro的亲和力降低约2.0 kcal / mol 。我们的结果可能有助于开发抑制SARS-CoV-2的潜在药物。