Discovering broad-spectrum inhibitors for SARS-CoV-2 variants: a cheminformatics and biophysical approach targeting the main protease

The COVID-19 pandemic caused by SARS-CoV-2 still lacks effective antiviral drugs. Therefore, a thorough receptor-based virtual screening study was conducted to screen different natural and synthetic drug libraries, such as the Asinex Antiviral, Seaweed Metabolite Database, Medicinal Fungi Secondary Metabolite and Therapeutics Library, and Comprehensive Marine Natural Products Database comprising 6,827, 1,191, 1,830, and 45,000 compounds, respectively, against the main protease enzyme of SARS-CoV-2. Accordingly, three drug molecules (BBB-26580140, BDE-32007849, and LAS-51378804) are highlighted as the best binding molecules to the main protease S1 pocket. The docking binding energy scores of BBB-26580140, BDE-32007849, and LAS-51378804 were −13.02, −13.0, and −12.56 kcal/mol, respectively. Compared to the control Z1741970824 molecule with a binding energy score of −11.59 kcal/mol, the lead structures identified herein showed robust hydrophilic and van der Waals interactions with the enzyme active site residues, such as His41 and Cys145, and achieved highly stable binding modes. The simulations showed a stable structure of the main protease enzyme with the shortlisted leads in the pocket, and the network of binding interactions remained intact during the simulations. The overall molecular mechanics with generalized Born and surface area solvation binding energies of the BBB-26580140, BDE-32007849, LAS-51378804, and control molecules are −53.02, −56.85, −55.44, and −48.91 kcal/mol, respectively. Similarly, the net molecular mechanics Poisson–Boltzmann surface area binding energies of BBB-26580140, BDE-32007849, LAS-51378804, and control are −53.6, −57.61, −54.41, and −50.09 kcal/mol, respectively. The binding entropy energies of these systems showed lower free energies, indicating their stable nature. Furthermore, the binding energies were revalidated using the water swap method that considers the role of the water molecules in bridging the ligands to the enzyme active site residues. The compounds also revealed good ADMET properties and followed all major rules of drug-likeness. Thus, these compounds are predicted as promising leads and can be subjected to further experimental studies for evaluation of their biological activities.