Elucidation of the inhibitory activity of plant-derived SARS-CoV inhibitors and their potential as SARS-CoV-2 inhibitors

Several drugs are now being tested as possible therapies due to the necessity of treating SARS-CoV-2 infection. Although approved vaccines bring much hope, a vaccination program covering the entire global population will take a very long time, making the development of effective antiviral drugs an effective solution for the immediate treatment of this dangerous infection. Previous studies found that three natural compounds, namely, tannic acid, 3-isotheaflavin-3-gallate and theaflavin-3,3-digallate, are effective proteinase (3CL^pro) inhibitors of SARS-CoV (IC₅₀ <10 µM). Based on this information and due to the high sequence identity between SARS-CoV and SARS-CoV-2 3CL^pro, these three compounds could be candidate inhibitors of SARS-CoV-2 3CL^pro. This paper explores the structural and energetic features that guided the molecular recognition of these three compounds for dimeric SARS-CoV-2 and SARS-CoV 3CL^pro, the functional state of this enzyme, using docking and MD simulations with the molecular mechanics-generalized-born surface area (MMGBSA) approach. Energetic analysis demonstrated that the three compounds reached good affinities in both systems in the following order: tannic acid > 3-isotheaflavin-3-gallate > theaflavin-3,3-digallate. This tendency is in line with that experimentally reported between these ligands and SARS-CoV 3CL^pro. Therefore, tannic acid may have clinical usefulness against COVID-19 by acting as a potent inhibitor of SARS-CoV-2 3CL^pro. Communicated by Ramaswamy H. Sarma