Safar M. Alqahtani ^*

• Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia

The COVID-19 pandemic caused by SARS-CoV-2 still lacks effective antiviral drugs. Therefore, in this work, a thorough receptor-based virtual screening study was conducted to screen different natural and synthetic drug libraries such as libraries named Asinex Antiviral, Seaweed Metabolite Database, Medicinal Fungi Secondary Metabolite and Therapeutics Library (MFSMTL), and Comprehensive Marine Natural Products Database (CMNPD) having 6827, 1191, 1830, and 45000 compounds respectively against the SARS-CoV-2 main protease enzyme. By doing so, three drug molecules (BBB-26580140, BDE-32007849, LAS-51378804) were highlighted as the best binding molecules to the main protease S1 pocket. The docking binding energy score of BBB-26580140, BDE-32007849, and LAS-51378804 was -13.02 kcal/mol, -13.0 kcal/mol and -12.56 kcal/mol, respectively. Compared to the control (Z1741970824, binding energy score of -11.59 kcal/mol), the lead structures identified herein reported robust hydrophilic and van der Waals interactions with the enzyme active site residues such as His41 and Cys145 and achieved highly stable binding mode. The simulation protocol noticed a stable structure of the main protease enzyme with shortlisted leads in its pocket and the binding interactions network remained intact during the simulation time. The overall net MM-GBSA binding energy of BBB-26580140, BDE-32007849, LAS-51378804, and control is -53.02 kcal/mol, -56.85 kcal/mol, -55.44 kcal/mol, and -48.91 kcal/mol, respectively. Similarly, the net MM-PBSA binding energy of BBB-26580140 was -53.6 kcal/mol, BDE-32007849 was -57.61 kcal/mol, LAS-51378804 was -54.41 kcal/mol, and control was -50.09 kcal/mol. The binding entropy energy of the systems unveiled the presence of less freedom energy classifying the systems of a stable nature. Further, the binding energies were revalidated by the Water Swap method, which considered the role of 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, it can be predicted the compounds are promising leads and can subjected to experimental studies for evaluation of their biological activities.