Pharmacokinetics, molecular docking, and molecular dynamics simulation unveil novel lichen-derived scaffolds...

Antimicrobial resistance (AMR) is a major threat to global health. It reduces the effectiveness of current antibiotics and treatment for infectious diseases. The rise in AMR is mainly due to the overuse of antibiotics and the increased adaptability of harmful microorganisms. Among resistant bacteria, Methicillin-Resistant Staphylococcus aureus (MRSA) can resist an array of antibiotics. A key factor in resistance of MRSA is Penicillin-binding protein 2a (PBP2a). This protein decreases the effectiveness of β-lactam antibiotics and makes treatment more difficult. Therefore, finding new inhibitors that target PBP2a is crucial. In this study, Parmotrema perlatum, a himalayan lichen that has not been extensively studied for its antimicrobial properties, was chosen.

Phytochemical research identified methyl orsellinate (MO) as a prominent secondary metabolite with antioxidant and antibacterial activities. However, initial docking analysis showed that MO had weak binding affinity for PBP2a. The molecular structure of MO was modified using a scaffold-morphing method to create a series of structural analogues. Molecular docking was conducted to assess their binding affinities and inhibitory potential. A detailed ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) screening followed, to evaluate their pharmacokinetic and toxicity profiles. The stability of the top protein-ligand complexes using molecular dynamics (MD) simulations was assessed.

MO-1 showed strong binding interactions with PBP2a and maintained stable trajectories throughout the simulation. Furthermore, MM/PBSA analysis indicated negative ΔG values, suggesting favourable binding. Overall, these results indicate that MO-derived analogue, MO-1 could be a computationally prioritised candidate for developing new therapies targeting MRSA. This study aims to open a new avenue to approach the problem of AMR with production of ethno-medicines using MO-1 to create effective therapies against MRSA and help reduce dependency on antibiotics.