Elucidating the Quorum Sensing Inhibitory Mechanism of Flavonoid Quercetin by Molecular Docking, Molecular Dynamics Simulation, and MM-GBSA Study

Quercetin, a naturally occurring flavonoid found in plants, has gained attention as a powerful quorum sensing (QS) inhibitor. However, the exact mechanism of its inhibitory effects is not yet fully understood. The Pseudomonas quinolone signal PQS has been demonstrated to trigger the formation of outer-membrane vesicles (OMVs) in Gram-negative bacteria, including Pseudomonas aeruginosa. Various other bacterial species have also responded to PQS, suggesting a shared biophysical mechanism. This study investigated the quorum-sensing inhibitory properties of Quercetin by assessing its binding affinity to the active site of PqsE (PDB: 2Q0J) using molecular docking, molecular dynamics simulations, and MM-GBSA assay. The results of molecular docking envisaged that the compound interacts with the target protein PqsE, exhibiting a binding energy value of (-7.46 kcal/mol; IC=3.39 µM). MD simulation over a time scale of 100 ns corroborated the interaction results obtained from molecular docking between Quercetin and the PqsE protein. In addition, MM-GBSA calculations confirmed that the compound Quercetin has high binding energies of -19.532 ± 16.048 Kcal/mol against PqsE protein. The strong binding affinity of the flavonoid quercetin, as demonstrated by in silico inhibition experiments, indicates its potential as a quorum-sensing inhibitor and its promise as a synergistic component in non-antibiotic therapeutic options for treating infections. Our findings reveal the molecular interactions involved in inhibiting the PqsE protein, resulting in blocking bacterial outer membrane vesicles. This sheds light on the essential aspects of the biophysical process underlying the antibacterial effects induced by Quercetin by inhibiting quorum sensing.