Abstract
COVID-19 pandemic caused by SARS-CoV-2 led to the research aiming to find the inhibitors of this virus. Towards this world problem, an attempt was made to identify SARS-CoV-2 main protease (M(pro)) inhibitory peptides from ricin domains. The ricin-based peptide from barley (BRIP) was able to inhibit M(pro) in vitro with an IC(50) of 0.52 nM. Its low and no cytotoxicity upto 50 µM suggested its therapeutic potential against SARS-CoV-2. The most favorable binding site on M(pro) was identified by molecular docking and steered molecular dynamics (MD) simulations. The M(pro)-BRIP interactions were further investigated by evaluating the trajectories for microsecond timescale MD simulations. The structural parameters of M(pro)-BRIP complex were stable, and the presence of oppositely charged surfaces on the binding interface of BRIP and M(pro) complex further contributed to the overall stability of the protein-peptide complex. Among the components of thermodynamic binding free energy, Van der Waals and electrostatic contributions were most favorable for complex formation. Our findings provide novel insight into the area of inhibitor development against COVID-19.