Molecular insights into natural product compounds targeting papain protease of SARS-CoV-2 through molecular dynamics simulation

Over 5 years, COVID-19 has spread globally, causing 774 million cases and 7 million deaths. Challenges such as ineffective treatments, vaccine hesitancy, gene mutations, and high drug costs highlight the need for new inhibitors. SARS-CoV-2’s papain-like protease (PLpro), crucial for viral replication, is a promising target for treatment. This study used structure-based virtual screening, pharmacokinetic analysis, molecular docking, and molecular dynamics (MD) simulation to identify phytochemical inhibitors of PLpro. From 45 Thai medicinal plant-derived phytochemicals, 27 compounds met Lipinski’s rule of 5 criteria and underwent ADMET and molecular docking analysis. The top 15% of compounds with the highest docking scores, (3R)-7,4′-dihydroxy-8-methoxyhomoisoflavane, bergenin, capparispine, and feruloyl tyramine, were subjected to 100 ns MD simulations to assess their stability and interactions with SARS-CoV-2 PLpro. Compounds (3R)-7,4′-dihydroxy-8-methoxyhomoisoflavane, bergenin, and capparispine showed extensive interactions with key PLpro residues, including D164, R166, P247, P248, Y264, Y268, Y273 Q269, and D302 through hydrogen bonding and hydrophobic interactions. In contrast, feruloyl tyramine exhibited weaker interaction, forming only non-polar contacts with PLpro residues P247, P248, Y264, and Y268. MM/GBSA analysis confirmed strong and favorable binding energies for (3R)-7,4′-dihydroxy-8-methoxyhomoisoflavane, bergenin, and capparispine, suggesting their potential as PLpro inhibitors. This information could contribute in the developing of effective SARS-CoV-2 inhibitors.