Division of Applied Life Science, BK21 Program, Systems and Synthetic Agrobiotech Center, Research Institute of Natural Science, Gyeongsang National University, Jinju, Republic of Korea.
PLoS One. 2012;7(4):e34593. doi: 10.1371/journal.pone.0034593. Epub 2012 Apr 5.
Human leukotriene A4 hydrolase (hLTA4H) is a bi-functional enzyme catalyzes the hydrolase and aminopeptidase functions upon the fatty acid and peptide substrates, respectively, utilizing the same but overlapping binding site. Particularly the hydrolase function of this enzyme catalyzes the rate-limiting step of the leukotriene (LT) cascade that converts the LTA4 to LTB4. This product is a potent pro-inflammatory activator of inflammatory responses and thus blocking this conversion provides a valuable means to design anti-inflammatory agents. Four structurally very similar chemical compounds with highly different inhibitory profile towards the hydrolase function of hLTA4H were selected from the literature. Molecular dynamics (MD) simulations of the complexes of hLTA4H with these inhibitors were performed and the results have provided valuable information explaining the reasons for the differences in their biological activities. Binding mode analysis revealed that the additional thiophene moiety of most active inhibitor helps the pyrrolidine moiety to interact the most important R563 and K565 residues. The hLTA4H complexes with the most active compound and substrate were utilized in the development of hybrid pharmacophore models. These developed pharmacophore models were used in screening chemical databases in order to identify lead candidates to design potent hLTA4H inhibitors. Final evaluation based on molecular docking and electronic parameters has identified three compounds of diverse chemical scaffolds as potential leads to be used in novel and potent hLTA4H inhibitor design.
人白细胞三烯 A4 水解酶（hLTA4H）是一种双功能酶，分别催化脂肪酸和肽底物的水解酶和氨肽酶功能，利用相同但重叠的结合位点。特别是该酶的水解酶功能催化了白细胞三烯（LT）级联反应的限速步骤，将 LTA4 转化为 LTB4。该产物是炎症反应的一种有效的促炎激活剂，因此阻断这种转化为设计抗炎剂提供了一种有价值的手段。从文献中选择了四种结构非常相似但对 hLTA4H 的水解酶功能具有高度不同抑制谱的化学化合物。对 hLTA4H 与这些抑制剂的复合物进行了分子动力学（MD）模拟，结果提供了有价值的信息，解释了它们在生物学活性上差异的原因。结合模式分析表明，最活跃抑制剂的额外噻吩部分有助于吡咯烷部分与最重要的 R563 和 K565 残基相互作用。与最活跃化合物和底物的 hLTA4H 复合物被用于开发混合药效团模型。这些开发的药效团模型用于筛选化学数据库，以鉴定潜在的先导候选物，用于设计有效的 hLTA4H 抑制剂。基于分子对接和电子参数的最终评估已确定三种具有不同化学支架的化合物为潜在的先导化合物，可用于新型和有效的 hLTA4H 抑制剂设计。
