The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC₅₀ less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC₅₀ values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.

中文翻译：

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使用虚拟筛选程序发现新型有效的可逆和不可逆的髓过氧化物酶抑制剂

血红素酶髓过氧化物酶（MPO）通过杀微生物活性氧化剂的形成参与先天免疫防御机制。但是，已经有证据表明，MPO衍生的氧化剂有助于炎症性疾病的传播。由于循环的MPO的有害作用，因此对开发新型有效和特异性抑制剂非常感兴趣。在这里，我们执行了一种新颖的虚拟筛选程序，具体取决于基于配体的药效团模型，然后进行基于结构的虚拟筛选。从一组727842个化合物开始，通过这种虚拟方法选择了28个分子，并在MPO上进行了体外测试。发现28种化合物中有12种的IC ₅₀小于5μM。最好的抑制剂是2-（7-甲氧基-4-甲基喹唑啉-2-基）胍（28）和（R）-2-（1-（（（2,3-二氢-1 H-咪唑-2-基）甲基）吡咯烷-3-基）-5-氟-1 H-苯并[ d ]咪唑（42）的IC ₅₀值分别为44和50 nM。关于抑制机理的研究表明，28是第一个有效的基于机理的抑制剂，并且以纳摩尔浓度不可逆地抑制MPO。