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<p><i>Pseudomonas aeruginosa</i> is regarded as the most opportunistic pathogen. It can induce ferroptosis in humans. It secretes a unique lipoxygenase (LOX) isoform, pLoxA that can oxidize polyenoic fatty acids. Unlike other lipoxygenases, pLoxA can oxygenate membrane phospholipids like phosphatidylethanolamine, leading to hemolysis of red blood cells (RBC). This functional overlap with human 15-LOX that uses the same substrate has provided a bottleneck to the discovery of pLoxA-specific inhibitors and there is an immediate need to find pLoxA specific drugs. The active site of pLoxA is much larger than LOX enzymes, reflecting its ability to accommodate bulky substrates, such as phospholipids. The molecular docking of two experimentally established inhibitors and the further molecular dynamics simulations provided possible key residues in the active site of pLoxA. Our study found that this region is essentially hydrophobic including His 377 and His 382 that are placed to the non-heme iron atom and help to stabilize the inhibitors in the binding site along with hydrophobic residues contribute well toward ligand interactions that involve Phe 415, Ile 416 and Leu 424. MD simulations showed that interactions with those residues were dynamic in nature. Main contribution to binding stability arose via π-π stacking, π-cation, and alkyl interactions.</p> Graphical Abstract <p></p>

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Computational insights into the targeted inhibition of lipoxygenase in Pseudomonas aeruginosa: hints for drug design

  • 期刊论文

  • 发表日期：

    2025年3月4日

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  • Sahanawaz Parvez,
  • Sonam Grewal,
  • Anamika Kumari,
  • Polamarasetty Aparoy

摘要

Pseudomonas aeruginosa is regarded as the most opportunistic pathogen. It can induce ferroptosis in humans. It secretes a unique lipoxygenase (LOX) isoform, pLoxA that can oxidize polyenoic fatty acids. Unlike other lipoxygenases, pLoxA can oxygenate membrane phospholipids like phosphatidylethanolamine, leading to hemolysis of red blood cells (RBC). This functional overlap with human 15-LOX that uses the same substrate has provided a bottleneck to the discovery of pLoxA-specific inhibitors and there is an immediate need to find pLoxA specific drugs. The active site of pLoxA is much larger than LOX enzymes, reflecting its ability to accommodate bulky substrates, such as phospholipids. The molecular docking of two experimentally established inhibitors and the further molecular dynamics simulations provided possible key residues in the active site of pLoxA. Our study found that this region is essentially hydrophobic including His 377 and His 382 that are placed to the non-heme iron atom and help to stabilize the inhibitors in the binding site along with hydrophobic residues contribute well toward ligand interactions that involve Phe 415, Ile 416 and Leu 424. MD simulations showed that interactions with those residues were dynamic in nature. Main contribution to binding stability arose via π-π stacking, π-cation, and alkyl interactions.

Graphical Abstract