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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.
摘要：
硫氰酸,铜绿假单胞菌产生的氧化还原活性吩嗪色素，抑制5-脂氧合酶（5-LOX）活性。然而,由于其产生超氧自由基和H2O2的能力，绿脓苷是否可以通过在活性位点结合来直接阻断酶活性仍然是一个问题。为了表征这种机制，我们进行了分子对接和分子动力学模拟，并进行了分子力学泊松-玻尔兹曼表面积（MMPBSA）结合能研究。研究结果表明，绿脓苷在5-LOX的活性位点是动态稳定的，其MMPBSA结合能（-84.720kJ/mol）与5-LOX标准抑制剂zileuton（-72.729kJ/mol）相当。使用其他三种吩嗪衍生物-1-羟基吩嗪的类似研究，吩嗪-1-羧酸和吩嗪-1-甲酰胺-也显示出令人鼓舞的结果。根据这些证据,我们假设作为概念的证明，通过直接结合在活性位点并阻断底物的酶催化，绿脓苷和这些吩嗪衍生物具有抑制5-LOX活性的潜力。考虑到5-LOX抑制剂在炎症性疾病如哮喘和类风湿性关节炎中的潜力，本研究的发现为吩嗪衍生物在针对5-LOX的基于结构的药物设计中的探索开辟了道路。由RamaswamyH.Sarma沟通。
