Mechanistic insights into 5-lipoxygenase inhibition by pyocyanin: a molecular docking and molecular dynamics study

Pyocyanin, a redox-active phenazine pigment produced by <i>Pseudomonas aeruginosa</i>, inhibits 5-lipoxygenase (5-LOX) activity. However, whether pyocyanin can directly block the enzymatic activity by binding at the active site still remains a question because of its ability to produce superoxide radicals and H₂O₂. With the objective of characterizing this mechanism, we carried out molecular docking and molecular dynamics simulations and performed Molecular Mechanics Poisson-Boltzmann surface area (MMPBSA) binding energy studies. The results of the study revealed that pyocyanin is dynamically stable at the active site of 5-LOX and its MMPBSA binding energy (−84.720 kJ/mol) is comparable to that of the 5-LOX standard inhibitor zileuton (−72.729 kJ/mol). Similar studies using three other phenazine derivatives − 1-hydroxyphenazine, phenazine-1-carboxylic acid and phenazine-1-carboxamide – also showed encouraging results. In light of this evidence, we postulate as a proof of concept that pyocyanin and these phenazine derivatives have the potential to inhibit 5-LOX activity by directly binding at the active site and blocking enzymatic catalysis of the substrate. Considering the potential of 5-LOX inhibitors in inflammatory diseases such as asthma and rheumatoid arthritis, the findings of this study open up the exploration of phenazine derivatives in structure-based drug design against 5-LOX. Communicated by Ramaswamy H. Sarma