Inhibition of acyl-homoserine-lactone synthase in Pseudomonas aeruginosa biofilms by 7-O-methyl-aromadendrin by using molecular docking and molecular dynamics simulation.

Abstract

This study investigates the potential of 7-O-methyl aromadendrin (7-OMA), a naturally occurring flavonoid-glycoside, as an inhibitor of acyl-homoserine-lactone (AHL) synthase in Pseudomonas aeruginosa, a key enzyme in quorum sensing and biofilm formation. Using molecular docking and molecular dynamics simulations, we evaluated the binding interactions and inhibitory effects of 7-OMA on AHL synthase. Molecular docking revealed a suitable binding affinity (-6.66 kcal/mol) between 7-OMA and the enzyme, with interactions at critical active site residues. Molecular dynamics simulations demonstrated that 7-OMA stabilizes the enzyme through hydrogen bonds and van der Waals interactions while enhancing its structural flexibility. The average RMSD of AHL synthase increased slightly in the presence of 7-OMA, indicating partial instability of the enzyme. Additionally, the average Rg value increased, suggesting that 7-OMA may expand the enzyme structure or reduce its compactness. MM-PBSA analysis confirmed the strength of these interactions, with favorable van der Waals and electrostatic contributions to the binding energy. These results suggest that 7-OMA disrupts the structural dynamics of AHL synthase, potentially inhibiting biofilm formation and reducing the virulence of Pseudomonas aeruginosa. The findings highlight the therapeutic potential of 7-OMA as a novel inhibitor of AHL synthase, offering a promising strategy to combat biofilm-associated infections. Future studies should focus on evaluating the bioavailability, in vivo efficacy, and clinical applicability of 7-OMA, as well as its broader activity against other multidrug-resistant pathogens.

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