In silico evaluation of physicochemical properties, drug-likeness, molecular docking, MD simulations and MM-PBSA energy calculations of bioactive compounds from antarctic sponge Suberites sp. against SARS-CoV-2 main proteases.

Building on prior research by Joe Bracegirdle and colleagues, who isolated sesterterpene compounds (1-11) from the Antarctic sponge Suberites sp., including Suberitenones A, B, and F, which exhibited antiviral activity against RSV, this study explored the potential of these compounds as inhibitors of the SARS-CoV-2 main proteases (PDB IDs: 6LU7 and 6W63) utilising in silico drug design approaches. All the ligands were subjected to molecular docking with the SARS-CoV-2 main protease. The results indicated significant binding affinities, ranging from - 6.1 to -7.6 kcal/mol for 6LU7 and - 6.8 to -8.2 kcal/mol for 6W63. Further assessment of their ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and drug-likeness revealed favourable pharmacokinetic characteristics for these compounds. Among them, Suberitenone E (2) and Suberitenone I (6) stood out as the most promising. Compound 2 exhibited a strong binding affinity of -8.2 kcal/mol with 6W63. In comparison, compound 6 showed an affinity of -7.6 kcal/mol with 6LU7, both demonstrating robust interactions with the SARS-CoV-2 main protease receptor and acceptable ADMET profiles. The stability and binding strength of these ligand-protease complexes were further confirmed through molecular dynamics simulations and MMPBSA energy calculations. Molecular dynamics simulations assessed the binding affinity of two compounds to the SARS-CoV-2 main protease receptors. Among the 11 ligands tested, compounds 2 and 6 exhibited superior binding affinity. This suggests their potential for modulating enzyme activity and potential relevance in COVID-19 treatment. The collective findings suggest that these compounds possess strong potential as natural antiviral agents. This study highlights compounds 2 and 6 as particularly promising drug leads, warranting further experimental validation through in vitro and in vivo studies to confirm their antiviral activity.