Natural Marine-derived Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease: A Comprehensive Computational Study

Background: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, highlights the urgent need for effective antiviral agents. The main protease [3-chymotrypsin-like protease (3CLpro)] of SARS-CoV-2 is crucial for viral replication and is a promising target for therapeutic intervention. Objectives: In this study, an in silico approach was employed to identify potential 3CLpro inhibitors from a library of 80 marine-derived natural compounds. Methods: Molecular docking was performed using AutoDock Vina to assess the binding affinity and interaction profiles of the compounds with the active site of 3CLpro. The top-scoring compounds were selected for molecular dynamics simulations using GROMACS to analyze the structural stability and dynamic behavior of the ligand-protease complexes. Results: Several compounds, particularly those from marine fungi and sponges, formed stable interactions with catalytic residues His41 and Cys145, maintaining conformational stability throughout 100 ns of simulation. In silico ADMET assessments were further performed to predict the pharmacokinetic properties of the docked compounds. Overall, molecular dynamics (MD) analysis showed that the dynamic properties of the protein alter significantly when it is in complex with the selected compounds. Conclusions: The findings in this study suggest that Isobutyrolactone II and Aspernolide A, marine natural products, could serve as promising lead compounds for the development of SARS-CoV-2 main protease inhibitors, warranting further experimental validation.