In silico Study of Phenol Explorer Database as Potential Inhibitors of Quorum-Sensing Regulated Pathogenicity in Pseudomonas aeruginosa

Abstract

Immunocompromised patients get Pseudomonas aeruginosa infections. P. aeruginosa's harmful effect is linked to quorum sensing (QS), which causes bacterial biofilm. Targeting QS is a promising novel method to treat P. aeruginosa infections, which are antibiotic-resistant. The Las system has garnered great interest due to LasR, the expedited gene during QS that regulates other virulence-associated genes. We used high-throughput virtual screening (VS) of Phenol Explorer to uncover a new category of LasR inhibitors that might be used as antagonists. Molecular docking-based VS against LasR (PDB: 2UV0) resulted in six best-scored compounds: Chrysin, Galangin, Coumestrol, 3',4',7- Trihydroxyisoflavanone, Dihydrodaidzein, Dihydroformononetin with docking score of -11.0 kcal/mol and a suitable ADMET profile. Six compounds were chosen for their lack of carcinogenicity in mice and rats, low molecular weight of 270 Da, and moderate to total solubility. Our current work shows that these six chemicals could block P. aeruginosa quorum sensing. Molecular dynamics investigations of a prospective therapeutic candidate (Chrysin) using Gromacs version 2022.2 demonstrated system stability; nonetheless, the antibiofilm assay showed a positive reaction against our in silico finding, suggesting a disturbance in quorum sensing regulating pathogenicity, i.e., biofilm formation. This study is the first to describe chrysin as a disruptor of quorum sensing signaling by inhibiting biofilm formation.