Combining SARS-CoV-2 proofreading exonuclease and RNA-dependent RNA polymerase inhibitors as a strategy to combat COVID-19: a high-throughput in silico screen

SARS-CoV-2 has infected millions of people worldwide. Currently, many clinical trials for drugs against COVID-19 are underway. Viral RNA-dependent RNA polymerase (RdRP) remains the target of choice for prophylactic or curative treatment of COVID-19. Nucleoside analogs are the most promising RdRp inhibitors and have shown effectiveness in vitro as well as in clinical settings. One limitation of such RdRp inhibitors is removal of incorporated nucleoside analogs by SARS-CoV-2 exonuclease (ExoN). Thus, it accomplishes resistance to many of the RdRp inhibitors. We hypothesize that in the absence of highly efficient antivirals to treat COVID-19, combination drugs with RdRP and ExoN inhibitors will be a promising strategy to combat the disease. To repurpose drugs for COVID-19 treatment, 10,427 conformers of 2,240 approved drugs were screened against ExoN domain. The molecular docking approach helped us to identify Dexamethasone metasulfobenzoate, Conivaptan, Hesperidin and Glycyrrhizic acid as potential inhibitors of ExoN activity. We recommend further investigation of a combinational therapy using RdRp inhibitors with a repurposed ExoN inhibitor, deciphered through this study, as a potential COVID-19 treatment.
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