The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro)

With the potential for coronaviruses to re-emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS-CoV-2 is essential. The M-pro enzyme is crucial for disease progression and the virus's life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug-like molecules. Consequently, a commercially available ligand library containing similar to 7 million ligands was used to target site #2 via structure-based virtual screening. After extensive filtering, docking, and post-docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a M-pro non-competitive reversible inhibitor with a K-i of 115 mu M and an IC50 of 101.9 mu M. Throughout the 200 ns-long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, derivatives of our top hit were acquired for biological testing to gain deeper insights into their structure-activity relationship. To sum up, drug-like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic, and possibly other coronaviruses-caused diseases.

Automated summary

With structure-based virtual screening, a compound that can inhibit M-pro enzyme was discovered in this study. The compound showed good inhibitory effects in biological testing. Molecular dynamics simulations revealed the stable binding mode of the compound to the M-pro enzyme, forming interactions with specific residues at certain sites. The results suggest that drug-like allosteric inhibitors could be a promising additional weapon in combating the current pandemic and diseases caused by other coronaviruses.