Abstract

Given the highly contagious nature of SARS-CoV-2, it has resulted in an unprecedented number of COVID-19 infected and dead people worldwide. Since there is currently no vaccine available in the market, the identification of potential drugs is urgently needed to control the pandemic. In this study, 92 phytochemicals from medicinal plants growing in the Andean region were screened against SARS-CoV-2 3 C-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp) in their active sites through molecular docking. The cutoff values were set from the lowest docking scores of the FDA-approved drugs that are being used to treat COVID-19 patients (remdesivir, lopinavir, and ritonavir). Compounds with docking scores that were lower than cutoff values were validated by molecular dynamics simulation with GROMACS, using root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and intermolecular hydrogen bonds (H-bonds). Furthermore, binding free energies were estimated using the MM-PBSA method, and ADMET profiles of potential inhibitors were assessed. Computational analyses revealed that the interaction with hesperidin (theoretical binding energies, ΔG_bind = −15.18 kcal/mol to 3CLpro and ΔG_bind = −9.46 kcal/mol to RdRp) remained stable in both enzymes, unveiling its remarkable potential as a possible multitarget antiviral agent to treat COVID-19. Importantly, lupinifolin with an estimated binding affinity to 3CLpro higher than hesperidin (ΔG_bind = −20.93 kcal/mol) is also a potential inhibitor of the 3CLpro. These two compounds displayed suitable pharmacological and structural properties to be drug candidates, demonstrating to be worthy of further research.

Communicated by Ramaswamy H. Sarma

 抽象的

鉴于 SARS-CoV-2 的高度传染性，它已导致全球范围内出现前所未有的 COVID-19 感染和死亡人数。由于目前市场上还没有疫苗，因此迫切需要寻找潜在的药物来控制大流行。在这项研究中，通过分子对接，筛选了来自安第斯地区药用植物的 92 种植物化学物质，以对抗 SARS-CoV-2 3 C 样蛋白酶 (3CLpro) 和 RNA 依赖性 RNA 聚合酶 (RdRp) 的活性位点。截止值是根据 FDA 批准的用于治疗 COVID-19 患者的药物（瑞德西韦、洛匹那韦和利托那韦）的最低对接分数设定的。对接分数低于截止值的化合物通过 GROMACS 的分子动力学模拟进行验证，使用均方根偏差 (RMSD)、均方根波动 (RMSF)、回转半径 (Rg) 和分子间氢键 (H-)债券）。此外，使用 MM-PBSA 方法估算了结合自由能，并评估了潜在抑制剂的 ADMET 谱。计算分析表明，两种酶与橙皮苷的相互作用（理论结合能，对 3CLpro 的 ΔG_结合= -15.18 kcal/mol，对 RdRp 的 ΔG_结合= -9.46 kcal/mol）保持稳定，揭示了其作为多靶点抗病毒药物的非凡潜力治疗 COVID-19 的药物。重要的是，羽扇豆素对 3CLpro 的估计结合亲和力高于橙皮苷（ΔG_结合= -20.93 kcal/mol），也是 3CLpro 的潜在抑制剂。这两种化合物显示出适合作为候选药物的药理学和结构特性，值得进一步研究。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯