A deadly pandemic of COVID-19, an acute viral pneumonia, has erupted. Researchers are extensively looking forward to medication repurposing to identify new uses for FDA-approved or experimental drugs. A molecular modeling-based screening against COVID-19 Mpro (PDB: 6LU7) revealed that a group of medicines from the Drug Bank data source may have antiviral action in this research (Fig. 1). Forty-four of the Drug Bank's 8,823 most promising virtual hits were put through molecular dynamics simulations to see how strong their interactions with the SARS-CoV-2 Mpro active site were. MD findings point three drugs (DB04020, DB12411, and DB11779) with very low relative free energies for SARS-CoV-2 Mpro with interactions at His 41 and Met 49. MD simulations identified an additional interaction with Glu 166 which enhanced the binding affinity significantly. The 44 most promising hits from molecular docking-based virtual screening were subjected to QSAR analysis. The binding energy values of independent drug candidates were successfully predicted using PLS (partial-least-square) regression. Finally, the EC50 and CC50 of 10 therapeutic candidates were evaluated in cell culture against SARS-CoV-2. Nilotinib, Bemcentinib, and BMS-690514 had EC50 values of 1.1, 2.6, and 32.8 µM, respectively. In conclusion, the results of our computer-aided drug design provide a pathway for rational Mpro inhibitor drug design and the development of COVID-19 antiviral treatments.

Drug repurposing to identify nilotinib and BMS-690514 as potential SARS-CoV-2 main protease inhibitors: An insight from computational and In vitro study

ACS Spring 2022

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