Computational Screening of FDA‐Approved PPIs and PCABs against LasR Protein: Insights into Quorum Sensing Inhibition

Abstract Addressing bacterial infections caused by multi‐drug resistant bacteria is a global priority. One promising approach to overcoming the challenge of multi‐drug resistance involves inhibiting bacterial quorum sensing mechanisms. Quorum sensing (QS) inhibitors are emerging as potential alternatives to traditional antibiotics. In this study, FDA approved proton pump inhibitors (PPIs) and potassium‐competitive acid blockers (PCABs) were screened using in silico methods to evaluate their effectiveness in targeting the LasR protein which has a role in the QS mechanism of Pseudomonas aeruginosa . Tegoprazan and Lansoprazole exhibit strong binding affinity for the LasR protein, with binding free energies of −9.23 and −9.09 kcal/mol, respectively. Molecular dynamic (MD) simulations (100 ns) of the docked complexes revealed that Tegoprazan and Lansoprazole remained stably bound within the LasR protein's binding pocket most of the time of simulation. Throughout the simulation, the backbone of both complexes showed minor variations in RMSD and R g . The free energy landscape of the LasR‐Tegoprazan and LasR‐Lansoprazole complexes indicated strong stability. Both complexes exhibited excellent Molecular Mechanic/Poisson‐Boltzmann surface area (MM/PBSA) based binding free energies: −101.443 ± 12.845 kJ/mol for LasR‐Tegoprazan and −81.867 ± 14.633 kJ/mol for LasR‐Lansoprazole. In this study, we also investigate the DFT‐based electronic characteristics of these drugs in different solvents.