Pseudomonas aeruginosa Virulence Reduction Through Phytochemical Inhibition of Quorum Sensing Activity: A Molecular Docking and Molecular Dynamics Simulation Study

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that employs quorum sensing (QS) to regulate virulence and biofilm formation, leading to the emergence of multidrug resistance (MDR). This study aimed to identify phytocompounds from Cistus munbyi essential oil as potential inhibitors of the LasR QS receptor in P. aeruginosa . A library of 44 phytocompounds was screened through molecular docking studies targeting LasR and its variants (LasR‐Var1: R144I and LasR‐Var2: R180W). Cuminaldehyde and sabinyl acetate emerged as top candidates, exhibiting strong binding affinities comparable to the reference compound, N‐3‐oxo‐dodecanoyl‐L‐homoserine lactone (OdDHL). Molecular dynamics (MD) simulations over 200 ns confirmed stable interactions with key conserved residues, with cuminaldehyde demonstrating superior stability in LasR_Var2 (RMSD: 0.83 ± 0.33 nm). Density functional theory (DFT) analysis revealed favorable chemical reactivity for cuminaldehyde (energy gap: 5.071 eV) and sabinyl acetate (energy gap: 6.162 eV), supporting their potential as QS inhibitors. RMSD, RMSF, Rg, and SASA validated the structural stability of these complexes, while PCA‐based FEL analysis highlighted distinct conformational dynamics. These findings underscore the potential of cuminaldehyde and sabinyl acetate as anti‐QS agents to mitigate P. aeruginosa virulence and combat MDR. The study advocates for further in vitro validation to translate these in silico findings into novel phytochemical‐based therapeutics.