Repurposing benzimidazole and benzothiazole derivatives as potential inhibitors of SARS-CoV-2: DFT, QSAR, molecular docking, molecular dynamics simulation, and in-silico pharmacokinetic and toxicity studies

Mohapatra, Ranjan K.; Dhama, Kuldeep; El–Arabey, Amr Ahmed; Sarangi, Ashish K.; Tiwari, Ruchi; Emran, Talha Bin; Azam, Mohammad; Al-Resayes, Saud I.; Raval, Mukesh K.; Seidel, Veronique; Abdalla, Mohnad

Density Functional Theory (DFT) and Quantitative Structure-Activity Relationship (QSAR) studies were performed on four benzimidazoles (compounds 1-4) and two benzothiazoles (compounds 5 and 6), previously synthesized by our group. The compounds were also investigated for their binding affinity and interactions with the SARS-CoV-2 M(pro) (PDB ID: 6LU7) and the human angiotensin-converting enzyme 2 (ACE2) receptor (PDB ID: 6M18) using a molecular docking approach. Compounds 1, 2, and 3 were found to bind with equal affinity to both targets. Compound 1 showed the highest predictive docking scores, and was further subjected to molecular dynamics (MD) simulation to explain protein stability, ligand properties, and protein-ligand interactions. All compounds were assessed for their structural, physico-chemical, pharmacokinetic, and toxicological properties. Our results suggest that the investigated compounds are potential new drug leads to target SARS-CoV-2.