Computational identification of potential inhibitory compounds in Indian medicinal and aromatic plant species against major pathogenicity determinants of SARS-CoV-2

SARS-CoV-2 (COVID-19) viral pandemic has been reported across 223 countries and territories. Globalized vaccination programs alongside administration of repurposed drugs will assumingly confer a stronger and longer individual specific immune protection. However, considering possible recurrence of the disease via new variants, a conveniently deliverable phytopharmaceutical drug might be the best option for COVID-19 treatment. In the current study, the efforts have been made to identify potential leads for inhalation therapy as nasal swabs have been reported to transfer viral load prominently. In that direction, 2363 Essential oil (EOs) compounds from Indian medicinal and aromatic plants were screened through docking analysis and potential candidates were shortlisted that can interfere with viral pathogenicity. The main protease (M^pro) of SARS-CoV-2 interacted closely with jatamansin (JM), 6,7-dehydroferruginol (FG) and beta-sitosterol (BS), while Papain-like Protease (PL^pro) with friedelane-3-one (F3O) and lantadene D (LD) independently. Reduced Lantadene A (LAR) exhibited preferable interaction with RNA-dependent-RNA-polymerase (RdRp) whereas Lantadene A (LA) with RdRp and spike-glycoprotein (SG-pro) both target proteins. When compared against highest binding affinity conformations of well-known inhibitors of targets, these prioritized compounds conferred superior or comparable SARS-CoV-2 protein inhibition. Additionally, promising results were noted from pharmacokinetics prediction for all shortlisted compounds. Besides, molecular dynamics simulation for 100 ns in two replicates and binding free energy analysis revealed the stability of complexes with optimum compactness. To the best of our knowledge, the current investigation is a unique initial attempt whereby EO compounds have been computationally screened, irrespective of their known medicinal properties to fight COVID-19 infection. Communicated by Ramaswamy H. Sarma

严重急性呼吸综合征冠状病毒2型（SARS-CoV-2，即COVID-19）疫情已在全球223个国家和地区被报道。全球范围内的疫苗接种计划联合已获批老药的给药治疗，有望为个体提供更强效且更持久的特异性免疫保护。然而，考虑到新冠病毒可能通过新变异株引发疫情反复，使用给药便捷的植物源药物或许是COVID-19治疗的最优方案。
本研究旨在筛选可用于吸入治疗的潜在候选药物，因为已有研究表明鼻拭子是病毒载量传播的重要途径。基于此方向，本研究通过分子对接分析，对来自印度药用与芳香植物的2363种精油（Essential oil, EOs）化合物进行筛选，最终得到一批可干扰病毒致病性的潜在候选化合物。新冠病毒主要蛋白酶（main protease, M^pro）可与假荆芥内酯（jatamansin, JM）、6,7-去氢铁杉醇（6,7-dehydroferruginol, FG）以及β-谷甾醇（beta-sitosterol, BS）紧密结合；而木瓜蛋白酶样蛋白酶（Papain-like Protease, PL^pro）可分别与羽扇豆烷-3-酮（friedelane-3-one, F3O）和兰丹烯D（lantadene D, LD）结合。还原型兰丹烯A（Reduced Lantadene A, LAR）可与RNA依赖的RNA聚合酶（RNA-dependent-RNA-polymerase, RdRp）产生更优的相互作用；而兰丹烯A（Lantadene A, LA）则可同时与RdRp和刺突糖蛋白（spike-glycoprotein, SG-pro）这两种靶蛋白结合。与已报道的靶标经典抑制剂的最高结合亲和力构象相比，本研究筛选出的优先候选化合物对新冠病毒蛋白的抑制活性相当甚至更优。
此外，对所有入围化合物的药代动力学预测结果均表现良好。同时，通过两次重复的100纳秒分子动力学模拟以及结合自由能分析，证实了这些化合物与靶蛋白形成的复合物具有良好的构象稳定性与最优紧凑性。据我们所知，本研究是一项首创性的初步探索——未预先限定化合物是否具备抗新冠感染的已知药用活性，而是通过计算手段对精油类化合物进行了系统性筛选。由Ramaswamy H. Sarma转交。