In Silico Design and Molecular Docking of Flavone Compounds as Potential Enzyme Inhibitors Targeting Pseudomonas aeruginosa RmlA Enzyme in Fish Pathogenesis

Pseudomonas aeruginosa was found to be an opportunistic pathogen in aquaculture. It can cause severe diseases in fish and thus economic losses. The RmlA enzyme is essential for the biosynthesis of dTDP-L-rhamnose, and this compound plays a critical role in the bacterial virulence and its survival. Our study aimed to identify potential inhibitors of RmlA through molecular docking of 12 plant-derived flavonoid compounds. The three-dimensional crystal structure of RmlA was retrieved from the Protein Data Bank, and binding interactions were estimated using computational tools. The results of molecular docking of plant-derived flavonoid compounds showed strong binding affinities, and the most promising inhibitors were querciturone, isoquercetin, and spiraeoside, with energy affinities of –9.60kcal/ mol, –9.20kcal/ mol, and –8.60kcal/ mol, respectively. These compounds demonstrated interactions with key residues amino acids in the enzyme's active site, including ASP110, GLU161, and TYR145, forming diverse bonds such as hydrogen bonds, hydrophobic interactions, and electrostatic bonds. The inhibitors prevent the conformational transitions necessary for RmlA’s ordered bi-bi mechanism, thereby blocking the biosynthesis of bacterial dTDP-L-rhamnose. This study highlighted the potential of using flavonoid-derived compounds as effective natural inhibitors against P. aeruginosa to help develop novel therapeutic strategies against bacterial infections in aquaculture.