The lack of a vaccine or any effective treatment for the aggressive novel coronavirus disease (COVID-19) has created a sense of urgency for the discovery of effective drugs. Several repurposing pharmaceutical candidates have been reported or envisaged to inhibit the emerging infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their binding sites, binding affinities and inhibitory mechanisms are still unavailable. In this study, we use the ligand-protein docking program and molecular dynamic simulation to ab initio investigate the binding mechanism and inhibitory ability of seven clinically approved drugs (Chloroquine, Hydroxychloroquine, Remdesivir, Ritonavir, Beclabuvir, Indinavir and Favipiravir) and a recently designed α-ketoamide inhibitor (13b) at the molecular level. The results suggest that Chloroquine has the strongest binding affinity with 3CL hydrolase (Mpro) among clinically approved drugs, indicating its effective inhibitory ability for SARS-CoV-2. However, the newly designed inhibitor 13b shows potentially improved inhibition efficiency with larger binding energy compared with Chloroquine. We further calculate the important binding site residues at the active site and demonstrate that the MET 165 and HIE 163 contribute the most for 13b, while the MET 165 and GLN 189 for Chloroquine, based on residual energy decomposition analysis. The proposed work offers a higher research priority for 13b to treat the infection of SARS-CoV-2 and provides theoretical basis for further design of effective drug molecules with stronger inhibition.

中文翻译：

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新型冠状病毒（SARS-CoV-2）的潜在抑制剂

缺乏针对侵略性新型冠状病毒疾病（COVID-19）的疫苗或任何有效治疗方法，已经为发现有效药物带来了紧迫感。据报道或设想了几种重用的候选药物可以抑制严重的急性呼吸综合征冠状病毒2（SARS-CoV-2）的新兴感染，但它们的结合位点，结合亲和力和抑制机制仍然不可用。在这项研究中，我们使用配体-蛋白质对接程序和分子动力学模拟从头开始在分子水平上研究了七种临床批准的药物（氯喹，羟氯喹，伦德昔韦，利托那韦，贝克拉布韦，茚地那韦和法维吡韦）的结合机理和抑制能力。结果表明，氯喹与3CL水解酶（Mpro）具有最强的结合亲和力，表明其对SARS-CoV-2的有效抑制能力。然而，与氯喹相比，新设计的抑制剂13b显示出潜在的改善的抑制效率以及更大的结合能。我们根据残留能量分解分析，进一步计算了活性位点上重要的结合位点残基，并证明了MET 165和HIE 163对13b的贡献最大，而MET 165和GLN 189对氯喹的贡献最大。