Abstract

2020 will be remembered worldwide for the outbreak of Coronavirus disease (COVID-19), which quickly spread until it was declared as a global pandemic. The main protease (Mpro) of SARS-CoV-2, a key enzyme in coronavirus, represents an attractive pharmacological target for inhibition of SARS-CoV-2 replication. Here, we evaluated whether the anti-inflammatory drug Ibuprofen, may act as a potential SARS-CoV-2 Mpro inhibitor, using an in silico study. From molecular dynamics (MD) simulations, we also evaluated the influence of ionic strength on the affinity and stability of the Ibuprofen–Mpro complexes. The docking analysis shows that R(−)Ibuprofen and S(+)Ibuprofen isomers can interact with multiple key residues of the main protease, through hydrophobic interactions and hydrogen bonds, with favourable binding energies (−6.2 and −5.7 kcal/mol, respectively). MM-GBSA and MM-PBSA calculations confirm the affinity of these complexes, in terms of binding energies. It also demonstrates that the ionic strength modifies significantly their binding affinities. Different structural parameters calculated from the MD simulations (120 ns) reveal that these complexes are conformational stable in the different conditions analysed. In this context, the results suggest that the condition 2 (0.25 NaCl) bind more tightly the Ibuprofen to Mpro than the others conditions. From the frustration analysis, we could characterize two important regions (Cys44-Pro52 and Linker loop) of this protein involved in the interaction with Ibuprofen. In conclusion, our findings allow us to propose that racemic mixtures of the Ibuprofen enantiomers might be a potential treatment option against SARS-CoV-2 Mpro. However, further research is necessary to determinate their possible medicinal use.

Communicated by Ramaswamy H. Sarma

 抽象的

2020 年将因冠状病毒病 (COVID-19) 的爆发而被全世界铭记，该疾病迅速蔓延，直至被宣布为全球大流行。 SARS-CoV-2 的主要蛋白酶 (Mpro) 是冠状病毒中的一种关键酶，是抑制 SARS-CoV-2 复制的一个有吸引力的药理学靶点。在这里，我们通过计算机研究评估了抗炎药物布洛芬是否可以作为潜在的 SARS-CoV-2 Mpro 抑制剂。通过分子动力学（MD）模拟，我们还评估了离子强度对布洛芬-Mpro复合物的亲和力和稳定性的影响。对接分析表明，R(−)布洛芬和S(+)布洛芬异构体可以通过疏水相互作用和氢键与主蛋白酶的多个关键残基相互作用，并具有良好的结合能（分别为-6.2和-5.7 kcal/mol） ）。 MM-GBSA 和 MM-PBSA 计算证实了这些复合物在结合能方面的亲和力。它还表明离子强度显着改变了它们的结合亲和力。 MD 模拟（120 ns）计算出的不同结构参数表明，这些复合物在不同分析条件下构象稳定。在这种情况下，结果表明条件 2 (0.25 NaCl) 比其他条件更紧密地结合布洛芬与 Mpro。从挫败分析中，我们可以表征该蛋白质与布洛芬相互作用的两个重要区域（Cys44-Pro52 和连接环）。总之，我们的研究结果使我们能够提出，布洛芬对映体的外消旋混合物可能是针对 SARS-CoV-2 Mpro 的潜在治疗选择。然而，还需要进一步的研究来确定它们可能的药用用途。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯