Tetracyclines as Bioactive SARS-CoV-2 Main Protease Inhibitors: Insights into their Mechanism of Action using Free Energy Calculations and Molecular Dynamics Simulation

The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an extant threat against public health on a global scale. The SARS-CoV-2 main protease (M^pro) was identified as a key enzyme for processing the viral polyproteins to produce functional non-structural proteins. Thus, inhibiting M^pro activity could stop the spread of infection. In the following study, we investigated the M^pro inhibitory potential of clinically approved Tetracyclines, using free energy calculations and a molecular dynamics approach. In this study, 13 approved Tetracyclines were docked against the main protease of SARS CoV-2. Among the studied Tetracyclines, Lymecycline appear as potential inhibitor of this protease. When docked against M^pro crystal structure 6lu7, this compound revealed a minimum binding free energy of -8.87 kcal/mol with 168 binding modes detected in the binding substrate pocket. Further, molecular dynamics simulation and binding free energy calculations were performed to evaluate the dynamic behavior and stability of protein-ligand complex. The results obtained herein highlight the enhanced stability and good binding affinity of Lymecycline towards the target protein.