Molecular dynamics simulations and reverse docking approaches for identification of novel drug candidates against Aeromonas hydrophila

Aeromonas hydrophila ( A. hydrophila ) is a deadly pathogen which has the ability to spread disease to mammals, birds, and aquatic animals, resulting in severe zoonotic infections and high mortality rates. The growing prevalence of multidrug resistance among this bacterium has rendered many conventional antibiotics ineffective, emphasizing the critical need for novel therapeutic strategies. Natural compounds are a promising alternative because of their potential efficacy and lower toxicity when compared to synthetic medications. The aim of this study is to identify and evaluate natural metabolites as potential drug candidates against A. hydrophila using computational in silico methods. We assessed 100 plant metabolites for antibacterial activity, specifically targeting sensor histidine kinase (SHK) and UDP proteins that are critical for the pathogen's survival. Apigenin, Withaferin A, Kaempferol, and Norwogenin outperformed the others as pathogen inhibitors. Their binding affinities were compared to the control drug ciprofloxacin, and the top metabolites demonstrated significantly higher binding affinities. Among the top candidates, Withaferin A had a binding energy of −9.8 kcal/mol with SHK protein, which exceeded ciprofloxacin's binding energy of −7.7 kcal/mol. Molecular dynamics simulations confirmed the stability of these complexes, especially Apigenin, which had a low root mean square deviations (RMSD) of 0.3 nm over 100 ns. Additionally, all four metabolites met Lipinski's rule of five, indicating favorable therapeutic-like properties. The toxicity assessment reveals the candidates to be non-toxic, non-irritant, non-allergen and safe for medication. This study opens up possibilities for developing effective treatments for A. hydrophila . However, it is imperative to evaluate in-vivo trials to further analyze the efficiency and toxicity of these compounds.