Unveiling the potential of marine compounds as quorum sensing inhibitors targeting Pseudomonas aeruginosa's LasI: A computational study using molecular docking and molecular dynamics

Abstract

Antimicrobial resistance (AMR) poses a significant threat to global public health, with multidrug‐resistant Pseudomonas aeruginosa being a leading cause of mortality, accounting for 18%–61% of deaths annually. The quorum sensing (QS) systems of P. aeruginosa, particularly the LasI‐LasR system, play a crucial role in promoting biofilm formation and expression of virulent genes, which contribute to the development of AMR. This study focuses on LasI, the mediator of biofilm formation for identifying its inhibitors from a marine compound database comprising of 32 000 compounds using molecular docking and molecular simulation techniques. The virtual screening and docking experiments demonstrated that the top 10 compounds exhibited favorable docking scores of <−7.19 kcal/mol compared to the reported inhibitor 3,5,7‐Trihydroxyflavone with a docking score of −3.098 kcal/mol. Additionally, molecular mechanics/Poisson‐Boltzmann generalized born surface area (MM‐GBSA) analyses were conducted to assess these compounds' suitability for further investigation. Out of 10 compounds, five compounds demonstrated high MM‐GBSA binding energy (<−35.33 kcal/mol) and were taken up for molecular dynamics simulations to evaluate the stability of the protein‐ligand complex over a 100 ns period. Based on root mean square deviation, root mean square fluctuation, radius of gyration, and hydrogen bond interactions analysis, three marine compounds, namely MC‐2 (CMNPD13419) and MC‐3 (CMNPD1068), exhibited consistent stability throughout the simulation. Therefore, these compounds show potential as promising LasI inhibitors and warrant further validation through in vitro and in vivo experiments. By exploring the inhibitory effects of these marine compounds on P. aeruginosa's QS system, this research aims to contribute to the development of novel strategies to combat AMR.