COVID-19 is a disease that puts most of the world on lockdown and the search for therapeutic drugs is still ongoing. Therefore, this study used in silico screening to identify natural bioactive compounds from fruits, herbaceous plants, and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2 (PDB: 6LU7). We have used extensive screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME, molecular dynamics (MD) simulation, and MM/GBSA. A total of 17 compounds were shortlisted using Lipinski’s rule in which 5 compounds showed significant predicted antiviral activity values. Among these 5, only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy of −9.22 and −8.00 kcal/mol, respectively, within the binding pocket of the M^pro catalytic residues (HIS 41 and CYS 145). These two compounds were further analyzed to determine their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective in developing therapeutic drugs to be used in clinical trials. MD simulations showed that protein–ligand complexes of Macrolactin A and Stachyflin with the target receptor (6LU7) were stable for 100 nanoseconds. The MM/GBSA calculations of M^pro–Macrolactin A complex indicated higher binding free energy (−42.58 ± 6.35 kcal/mol). Dynamic cross-correlation matrix (DCCM) and principal component analysis (PCA) on the residual movement in the MD trajectories further confirmed the stability of Macrolactin A bound state with 6LU7. In conclusion, this study showed that marine natural compound Macrolactin A could be an effective therapeutic inhibitor against SARS-CoV-2 protease (6LU7). Additional in vitro and in vivo validations are strongly needed to determine the efficacy and therapeutic dose of Macrolactin A in biological systems.

COVID-19 是一种使世界大部分地区处于封锁状态的疾病，并且仍在寻找治疗药物。因此，这项研究用于计算机筛选，以从水果、草本植物和海洋无脊椎动物中鉴定能够抑制 SARS-CoV-2（PDB：6LU7）蛋白酶活性的天然生物活性化合物。我们使用了广泛的筛选策略，例如药物可能性、抗病毒活性值预测、分子对接、ADME、分子动力学 (MD) 模拟和 MM/GBSA。使用 Lipinski 规则筛选出总共 17 种化合物，其中 5 种化合物显示出显着的预测抗病毒活性值。在这 5 种化合物中，只有 2 种化合物 Macrolactin A 和 Stachyflin 在 M ^pro的结合口袋内显示出良好的结合能，分别为 -9.22 和 -8.00 kcal/mol催化残基（HIS 41 和 CYS 145）。进一步分析这两种化合物以确定它们的 ADME 特性。这两种化合物的 ADME 评估表明它们可以有效地开发用于临床试验的治疗药物。MD 模拟表明 Macrolactin A 和 Stachyflin 与目标受体 (6LU7) 的蛋白质-配体复合物在 100 纳秒内保持稳定。M ^pro的 MM/GBSA 计算–Macrolactin A 复合物显示出更高的结合自由能 (-42.58 ± 6.35 kcal/mol)。MD 轨迹中残余运动的动态互相关矩阵 (DCCM) 和主成分分析 (PCA) 进一步证实了 Macrolactin A 结合状态与 6LU7 的稳定性。总之，这项研究表明，海洋天然化合物 Macrolactin A 可能是一种有效的 SARS-CoV-2 蛋白酶（6LU7）治疗抑制剂。强烈需要额外的体外和体内验证来确定 Macrolactin A 在生物系统中的功效和治疗剂量。