Structure-based screening and molecular dynamics of phytophytochemicals against pseudomonas aeruginosa quorum sensing systems

Pseudomonas aeruginosa employs quorum sensing (QS) to regulate virulence and antibiotic resistance, making QS inhibition a promising anti-infective strategy. Here, we computationally evaluated three phytochemicals-baicalin, berberine, and cinnamaldehyde-as QS inhibitors targeting LasR, RhlR, and PqsR regulators. Molecular docking revealed berberine as the most potent PqsR binder (GScore: -6.801 kcal/mol), competitively displacing the native ligand HHQ, while baicalin showed broad-spectrum inhibition of PqsR/RhlR. Cinnamaldehyde exhibited moderate LasR antagonism. Molecular dynamics (100 ns) confirmed complex stability (RMSD < 2.5 Å) and identified key interactions: berberine formed a salt bridge with PqsR Asp264, while baicalin induced allosteric helix destabilization. Pharmacokinetic profiling showed that berberine is rapidly cleared (134.7 mL/min/kg) and poses a risk of drug-drug interactions due to CYP3A4 and CYP2D6 inhibition. This makes formulation strategies or analogue design more suitable than relying on metabolic inhibition. In contrast, baicalin has very poor absorption (bioavailability score: 0.11), indicating that nanoformulation is required to improve its uptake. Cinnamaldehyde demonstrated favourable drug-likeness but required structural optimization to mitigate aldehyde reactivity. This study provides in-silico mechanistic support for phytochemical-mediated QS inhibition in P. aeruginosa, with berberine emerging as a lead candidate for further development. Our integrative approach map water displacement hotspots in PqsR (GIST) and detect a baicalin-linked distal helix perturbation (DSSP) consistent with allostery, and bridges computational prediction and therapeutic design, offering new strategies to combat antimicrobial resistance through virulence attenuation.