In silico Binding and Interactions of Known Antivirals to the Dimer Pocket of the SARS-CoV-2 Main Protease

The devastating COVID-19 pandemic began in December 2019, catalyzed by the emergence of the SARS-CoV-2 beta-coronavirus strain. This inflicted global havoc, infecting over 767 million individuals and claiming more than 6.9 million lives by the end of 2023. Despite accelerated vaccine approvals significantly curbing infection rates and fatalities, the persistent spread of COVID-19 cases has been driven by evolving SARS-CoV-2 variants. The risk of future pandemics due to viral mutations emphasizes the urgent need for more effective antiviral drugs to prevent resistance. In this study, we explored the potential binding of small molecules to the dimer site of SARS-CoV-2 main protease (Mpro). We used the DogSiteScore program to predict the druggable sites, and Autodock Vina to evaluate the binding affinities of known antivirals. The results revealed that most of the antivirals exhibit higher binding affinities to the dimer site compared to the catalytic site. Notably, indinavir, nelfinavir, lopinavir, grazoprevir, and dolutegravir are among the top binders, surpassing - 10 kcal/mol in the dimer site. Meanwhile, these antivirals exhibited affinities to the catalytic site that did not exceed -8.7 kcal/mol. These findings highlight the promising potential of the dimer site as an alternative target for developing specific COVID-19 inhibitors.