Pharmacokinetics, molecular docking, and molecular dynamics simulation unveil novel lichen-derived scaffolds targeting PBP2a MRSA.

Introduction: 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 Materials and Methods: 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. Results and Discussion: 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.