Background: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has ravaged lives across the globe since December 2019, and new cases are still on the rise. Peoples' ongoing sufferings trigger scientists to develop safe and effective remedies to treat this deadly viral disease. While repurposing the existing FDA-approved drugs remains in the front line, exploring drug candidates from synthetic and natural compounds is also a viable alternative. This study employed a comprehensive computational approach to screen inhibitors for SARS-CoV-2 3CL-PRO (also known as the main protease), a prime molecular target to treat coronavirus diseases.

Methods: We performed 100 ns GROMACS molecular dynamics simulations of three high-resolution X-ray crystallographic structures of 3CL-PRO. We extracted frames at 10 ns intervals to mimic conformational diversities of the target protein in biological environments. We then used AutoDock Vina molecular docking to virtual screen the Sigma-Aldrich MyriaScreen Diversity Library II, a rich collection of 10,000 druglike small molecules with diverse chemotypes. Subsequently, we adopted in silico computation of physicochemical properties, pharmacokinetic parameters, and toxicity profiles. Finally, we analyzed hydrogen bonding and other protein-ligand interactions for the short-listed compounds.

Results: Over the 100 ns molecular dynamics simulations of 3CL-PRO's crystal structures, 6LZE, 6M0K, and 6YB7, showed overall integrity with mean Cα root-mean-square deviation (RMSD) of 1.96 (±0.35) Å, 1.98 (±0.21) Å, and 1.94 (±0.25) Å, respectively. Average root-mean-square fluctuation (RMSF) values were 1.21 ± 0.79 (6LZE), 1.12 ± 0.72 (6M0K), and 1.11 ± 0.60 (6YB7). After two phases of AutoDock Vina virtual screening of the MyriaScreen Diversity Library II, we prepared a list of the top 20 ligands. We selected four promising leads considering predicted oral bioavailability, druglikeness, and toxicity profiles. These compounds also demonstrated favorable protein-ligand interactions. We then employed 50-ns molecular dynamics simulations for the four selected molecules and the reference ligand 11a in the crystallographic structure 6LZE. Analysis of RMSF, RMSD, and hydrogen bonding along the simulation trajectories indicated that S51765 would form a more stable protein-ligand complexe with 3CL-PRO compared to other molecules. Insights into short-range Coulombic and Lennard-Jones potentials also revealed favorable binding of S51765 with 3CL-PRO.

Conclusion: We identified a potential lead for antiviral drug discovery against the SARS-CoV-2 main protease. Our results will aid global efforts to find safe and effective remedies for COVID-19.