In silico analysis of quorum sensing modulators: Insights into molecular docking and dynamics and potential therapeutic applications.

Quorum sensing (QS) regulates bacterial functions like virulence and biofilm formation, mediated by proteins such as LasI and QscR in Pseudomonas aeruginosa. This study investigates the structural dynamics of LasI and QscR proteins in complex with Sulfamerazine and Sulfaperin, using AiiA lactonase as a negative control, through molecular dynamics (MD) simulations to identify potential QS modulators. Molecular docking and MD simulations assessed binding affinity and structural dynamics, analyzing parameters like docking scores, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), principal component analysis (PCA), and covariance analysis. Sulfamerazine exhibited the highest binding affinity for LasI based on docking scores, indicating strong ligand-protein interactions. MD simulations revealed stability in the LasI-Sulfamerazine complex, with lower RMSD compared to LasI-Sulfaperin and QscR complexes. RMSF analysis indicated greater flexibility in ligand-binding regions of LasI-Sulfaperin and QscR complexes, suggesting weaker binding. SASA showed a decrease in solvent-accessible surface area for the LasI-Sulfamerazine complex, supporting a compact structure. Rg values confirmed this, with the LasI-Sulfamerazine complex being more compact (~2.00 nm) than QscR-ligand complexes (2.10-2.30 nm). PCA revealed significant conformational changes in the LasI-Sulfamerazine complex, with PC1 explaining 57.26% variance. Covariance analysis indicated stronger residue coupling in the LasI-Sulfamerazine complex, suggesting higher rigidity, while LasI-Sulfaperin and QscR complexes exhibited flexible dynamics. AiiA lactonase was used as a negative control due to its established quorum quenching activity, which hydrolyzes AHL molecules and disrupts QS signaling. Unlike LasI and QscR, AiiA does not rely on small molecule binding for activation. However, a known LasI or QscR inhibitor would have served as a more appropriate positive control, which will be considered in future studies. These findings suggest the LasI-Sulfamerazine complex's stability and rigidity make Sulfamerazine a promising QS modulator. Computational analyses highlight its potential to disrupt bacterial communication. Further experimental validation is needed to confirm its therapeutic implications.