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

Abstract

Pyocyanin, a redox-active phenazine pigment produced by Pseudomonas aeruginosa, 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

Keywords:

• Pyocyanin
• phenazine derivatives
• 5-LOX
• molecular docking
• molecular dynamics

Acknowledgements

The authors express their gratitude to Bhagawan Sri Sathya Sai Baba, the founder chancellor of the Sri Sathya Sai Institute of Higher Learning. The authors acknowledge COSMOS Lab, CRIF, SSSIHL for providing computational facilities and DBT-BIF for financial support. Besides, the authors thank Dr. Venketesh S, Mr. Prasanth Ghanta, Dr. K. N. Naresh, Dr. B. Siva Kumar and Dr. C. Sai Manohar of SSSIHL and Dr. Arvind Kumar (Postdoctoral fellow, Case Western Reserve University School of Medicine) for their support in carrying out this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

SBR designed and performed the experiments with assistance of Dr. ASV.

Additional information

Funding

This work was supported by Department of Biotechnology, Ministry of Science and Technology (BT/BI/25/063/2012 (BIF-SSSIHL)).