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

绿脓菌素（Pyocyanin）是铜绿假单胞菌（Pseudomonas aeruginosa）产生的一种具有氧化还原活性的吩嗪类色素，可抑制5-脂氧合酶（5-lipoxygenase，5-LOX）的活性。然而，由于绿脓菌素能够产生超氧自由基与过氧化氢（H₂O₂），其是否可通过结合于酶的活性位点直接阻断其酶促活性，目前仍有待明确。为阐明该作用机制，本研究开展了分子对接与分子动力学模拟，并完成了分子力学-泊松玻尔兹曼表面积法（Molecular Mechanics Poisson-Boltzmann surface area, MMPBSA）结合能分析。研究结果显示，绿脓菌素在5-LOX的活性位点处动态稳定，其MMPBSA结合能（-84.720 kJ/mol）与5-LOX标准抑制剂齐留通（zileuton）的结合能（-72.729 kJ/mol）相当。针对另外三种吩嗪衍生物——1-羟基吩嗪（1-hydroxyphenazine）、吩嗪-1-羧酸（phenazine-1-carboxylic acid）与吩嗪-1-甲酰胺（phenazine-1-carboxamide）开展的类似研究也得到了令人鼓舞的结果。基于上述证据，本研究作为概念验证提出假说：绿脓菌素及其这类吩嗪衍生物可通过结合于5-LOX的活性位点、阻断底物的酶催化过程，从而抑制其活性。鉴于5-LOX抑制剂在哮喘、类风湿关节炎等炎症性疾病中的应用潜力，本研究的发现为基于结构的5-LOX靶向吩嗪衍生物类药物开发开辟了探索方向。本文由Ramaswamy H. Sarma提交。