Identification of nsp16 inhibitors of SARS -CoV-2, SARS -CoV-1 and MERS-CoV from FDA-approved drugs using in silico and in vitro methods

The methyltransferase nsp16 is a key enzyme that catalyses coronavirus replication. In this study, we virtually screened 1577 FDA-approved drugs against nsp16 of SARS-CoV-2, SARS-CoV-1, and MERS-CoV to identify compounds potentially serving as pan-coronavirus inhibitors. Microscale thermophoresis (MST) was used to verify the in-silico results obtained by virtual drug screening, followed by molecular docking and molecular dynamics simulation to test the binding affinities between the target and the candidates. Finally, the candidates were tested against a clinical isolate of SARS-CoV-2 in cell culture. The MST binding assay and molecular docking results showed that four of the candidates showed strong binding affinities to nsp16 of one or two coronaviruses. Nilotinib and simeprevir interacted with nsp16 protein of all three coronaviruses, viz. , SARS-CoV-2, SARS-CoV-1, and MERS-CoV, suggesting their potential to act as pan-coronavirus inhibitors. The drugs inhibited the virus with IC 50 values ranging between 8.34 and 36.1 µM when tested against a clinical isolate of SARS-CoV-2 in cell culture. • The library of FDA-approved drugs was screened to identify pan-nsp16 inhibitors. • MST assay shows five candidates bind to nsp16s, two of them bound to all nsp16s. • Nilotinib and simeprevir are pan-coronaviral inhibitors candidates. • Both of the candidates show high binding affinity to nsp16s in silico and in vitro .