eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2026-03-20 19 1 292 306 10.13005/bpj/3353 70048 article Magesh Mohan 1 Renukadevi Jeyavelkumaran 2 Sanjay Valliappan 2 Sri Vaishnavi Velegatla 2 Shakthi Harikrishnan 2 Kadir Aravindan 2 Department of Pharmaceutical Chemistry, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical sciences (SIMATS), Chennai, India Department of Pharmaceutics, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical sciences (SIMATS), Chennai, India The escalating prevalence of multidrug-resistant (MDR) bacterial pathogens necessitates the development of molecular frameworks capable of attenuating virulence through non-bactericidal mechanisms. Targeting quorum sensing (QS) systems represents a sophisticated approach to disarm bacterial pathogenicity by modulating intercellular signaling networks. In this study, a rational molecular hybridization strategy was employed to design acridine–sulfamethoxazole conjugates as potential inhibitors of the LuxP receptor in Vibrio harveyi, a key mediator of autoinducer-2 (AI-2)–dependent communication.Computational evaluation integrating molecular docking, long-timescale molecular dynamics simulations, and free-energy analyses demonstrated that the hybrid scaffold exhibits exceptional binding competence and conformational stability within the LuxP binding pocket. The lead molecule, characterized by strong π–π stacking, hydrophobic encapsulation, and persistent hydrogen-bonding interactions with catalytic residues, induced pronounced conformational rigidity in the receptor microenvironment. Dynamic trajectory analyses confirmed structural equilibrium with minimal backbone deviation and a compact tertiary organization, indicating high structural persistence of the protein–ligand complex. Thermodynamic profiling further revealed a highly favorable interaction energy landscape, dominated by van der Waals and electrostatic stabilization, corroborating the hybrid’s strong binding affinity and kinetic resilience.These molecular insights elucidate a mechanism in which the acridine–sulfamethoxazole hybrid enforces conformational immobilization of LuxP, functionally impairing AI-2 recognition and signal relay. The hybrid scaffold thereby exemplifies a dual-action pharmacophoric design—capable of simultaneously modulating quorum-sensing and metabolic pathways—offering a mechanistically advanced paradigm for next-generation anti-virulence therapeutics against MDR bacterial infections. https://biomedpharmajournal.org/vol19no1/targeting-quorum-sensing-to-combat-multidrug-resistance-a-molecular-dynamics-study-of-acridine-sulfamethoxazole-hybrids/ GROMACS LuxI/LuxR Molecular docking Molecular dynamics simulation Multidrug resistance Quorum sensing