Abstract

The outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), represents a pandemic threat to global public health. To date, ∼530,000 people died of this disease worldwide. Presently, researchers/clinicians are adopting the drug repurposing strategy to combat this disease. It has also been observed that some repurposed anti-viral drugs may serve as potent inhibitors of SARS CoV-2 Mpro, a key component of viral replication. Apart from these anti-viral drugs, recently dexamethasone (an important corticosteroid) is effectively used to treat COVID-19 patients. However, the mechanism behind the mode of its action is not so clear. Additionally, the effect of other well-known corticosteroids to control this disease by inhibiting the proteolytic activity of Mpro is ambiguous. In this study, we have adopted computational approaches to understand these aspects. Six well-known corticosteroids (cortisone, hydrocortisone, prednisolone, methylprednisolone, betamethasone and dexamethasone) and two repurposed drugs (darunavir and lopinavir) against COVID-19 were subjected for molecular docking studies. Two of them (betamethasone and dexamethasone) were selected by comparing their binding affinities with selected repurposed drugs toward Mpro. Betamethasone and dexamethasone interacted with both the catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these two Mpro-corticosteroid complexes are more stable, experience less conformational fluctuations and more compact than Mpro-darunavir/lopinavir complexes. These findings were additionally validated by MM-GBSA analysis. This study provides corroboration for execution of anti-COVID-19 activity of dexamethasone. Our study also emphasizes on the use of another important corticosteroid (betamethasone) as potential therapeutic agent for COVID-19 treatment.

摘要

由严重急性呼吸综合征冠状病毒 2 (SARS CoV-2) 引起的 COVID-19 的爆发对全球公共卫生构成了大流行威胁。迄今为止，全世界约有 530,000 人死于这种疾病。目前，研究人员/临床医生正在采用药物再利用策略来对抗这种疾病。还观察到，一些重新利用的抗病毒药物可以作为 SARS CoV-2 Mpro（病毒复制的关键组成部分）的有效抑制剂。除了这些抗病毒药物外，最近地塞米松（一种重要的皮质类固醇）也有效地用于治疗 COVID-19 患者。然而，其作用方式背后的机制还不是很清楚。此外，其他众所周知的皮质类固醇通过抑制 Mpro 的蛋白水解活性来控制这种疾病的效果是模棱两可的。在这项研究中，我们采用计算方法来理解这些方面。六种著名的皮质类固醇（可的松、氢化可的松、强的松龙、甲基强的松龙、倍他米松和地塞米松）和两种针对 COVID-19 的再利用药物（地瑞那韦和洛匹那韦）进行了分子对接研究。其中两种（倍他米松和地塞米松）是通过将它们与选定的重新利用药物对 Mpro 的结合亲和力进行比较来选择的。倍他米松和地塞米松与 Mpro 的两个催化残基（His41 和 Cys145）相互作用。分子动力学研究进一步表明，这两种 Mpro-皮质类固醇复合物比 Mpro-darunavir/lopinavir 复合物更稳定、构象波动更少且更紧凑。MM-GBSA 分析进一步验证了这些发现。该研究为地塞米松的抗 COVID-19 活性的执行提供了佐证。我们的研究还强调使用另一种重要的皮质类固醇（倍他米松）作为 COVID-19 治疗的潜在治疗剂。