Computational Screening of Natural Products Identifies Potential PqsR Inhibitors Targeting Pseudomonas aeruginosa Quorum Sensing

Abstract

The rise of multidrug‐resistant (MDR) bacteria poses a serious global health threat. Pseudomonas aeruginosa employs quorum sensing (QS) to regulate virulence, making QS inhibition a promising anti‐virulence strategy. Here, 4,687 plant‐derived natural compounds were computationally screened against PqsR, a key transcriptional regulator of PQS‐mediated virulence. A hierarchical docking workflow was followed by 100‐ns molecular dynamics (MD) simulations to evaluate binding stability. Five compounds Glucosylvitexin, Isorhoifolin, 1,4‐dicaffeoylquinic acid, 1,3‐dicaffeoylquinic acid, and Steppogenin showed favorable binding scores and stable interactions within the PqsR binding pocket. Among these, Steppogenin emerged as the most promising lead based on its binding behavior, dynamic stability, and predicted drug‐like properties. Steppogenin showed a GlideScore of –8.703 kcal/mol, molecular weight of 288.25 Da, consensus LogP of 1.44, and a topological polar surface area of 107.22 Å 2 . It showed high predicted gastrointestinal absorption, no Lipinski‐rule violations, and a bioavailability score of 0.55. It was predicted to be non‐BBB permeant and inactive across the evaluated toxicity endpoints. Overall, Steppogenin represents a promising natural‐product scaffold for further experimental evaluation as a potential PqsR antagonist. Direct binding and functional assays are required for validation.