From Code to Cure: Computational Identification of LasR Inhibitors to Combat Quorum Sensing in P. aeruginosa

Biofilm formation by Pseudomonas aeruginosa (PA) poses a significant challenge in clinical settings due to its contribution to chronic infections and antibiotic resistance. Quorum sensing (QS), particularly regulated by the LasR receptor, plays a crucial role in biofilm development and virulence. In this study, an integrative in silico approach was employed to identify potential LasR inhibitors. Molecular docking predicted binding affinities of candidate molecules, followed by molecular dynamics simulations to assess complex stability in dynamic system. Druggability analysis, quantum mechanical evaluation via density functional theory, and binding free energy calculations refined the selection, yielding six promising inhibitors. Among these, compounds 26529, 22498, and 25412 showed strong binding within the LasR ligand-binding domain, engaging key residues such as Tyr56, Trp60, Asp73, and Ser129. Notably, compound 26529 exhibited an additional pi-cation interaction with Trp88 which has higher bond energy than typical hydrogen bonds, setting it apart as the lead molecule. ADMET profiling further confirmed their favorable pharmacokinetic and toxicity properties, selecting the most drug-like candidates. The findings align with previous reports targeting LasR to attenuate PA virulence and biofilm formation. However, experimental validation remains essential to confirm their therapeutic efficacy. Overall, this study highlights promising QS inhibitors as potential anti-virulence agents against PA.