In Silico Multi-Target Inhibition of Pseudomonas aeruginosa MexAB-OprM Efflux Pump and LasR Receptor by Eugenol Derivatives

Abstract Multidrug-resistant Pseudomonas aeruginosa poses a critical global healthcare threat driven by active MexAB-OprM efflux pumps and LasR quorum-sensing virulence networks. Simultaneously inhibiting both resistance and virulence pathways represents a promising therapeutic approach to restore antibiotic efficacy. In this study, we evaluated parent eugenol and five structural derivatives (isoeugenol, eugenyl acetate, methyleugenol, zingerone, and estragole) using an in silico multi-target molecular docking and ADMET profiling framework. Protocol validation confirmed docking accuracy with root-mean-square deviation (RMSD) values below 2.0 Å. Molecular docking revealed that eugenyl acetate and zingerone exhibited superior thermodynamic binding affinities (–6.8 to –7.8 kcal/mol) compared to parent eugenol (–5.2 to –5.6 kcal/mol) across both LasR (PDB: 2UV0) and MexAB-OprM (PDB: 2DHH) active sites. Key hydrogen bonding and hydrophobic interactions were established with critical catalytic residues (Tyr56, Trp60, Asp73, Thr75, Ser129 in LasR; Arg76, Phe138, Asn140 in MexAB-OprM). Pharmacokinetic profiling confirmed zero Lipinski rule violations and high gastrointestinal absorption (94.5%–96.1%). These findings highlight eugenol-derived scaffolds as potent dual-action botanical adjuvants against multidrug-resistant P. aeruginosa.