In silico screening of phenolic compounds as potential inhibitors of the mexab-oprm efflux pump of Pseudomonas aeruginosa
Abstract
ABSTRACT The therapeutic efficacy against Gram-negative infections is increasingly compromised by multidrug resistance, largely driven by the active expulsion of antimicrobials. In Pseudomonas aeruginosa , the MexAB-OprM transporter is the primary efflux system underlying this phenotype. Although Efflux Pump Inhibitors represent a promising strategy to restore antibiotic susceptibility, the clinical translation of synthetic candidates has been limited by toxicity, highlighting the need for safer alternatives. This study aimed to systematically identify natural phenolic compounds with inhibitory potential against the MexB subunit. A hierarchical virtual screening pipeline was applied to the Phenol-Explorer database. Initially, compounds were filtered based on drug-likeness criteria. Binding affinities were subsequently evaluated by molecular docking using AutoDock Vina. Docking results were analyzed through clustering based on binding scores and conformational RMSD. Molecular dynamics simulations were then performed to assess the structural stability of the top-ranked complexes. From an initial set of 484 compounds, 100 satisfied the pharmacokinetic constraints. Based on these docking outcomes, ligands were independently prioritized according to either favorable binding energies or low RMSD dispersion, yielding 23 candidates for molecular dynamics simulations. Trajectory analyses identified conidendrin, avenanthramide 2p, eriodictyol, galangin, and syringaresinol as the most…
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