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