N-Substituted 5-(1H-Indol-2-yl)-2-methoxyanilines Are Allosteric Inhibitors of the Linoleate Oxygenase Activity of Selected Mammalian ALOX15 Orthologs: Mechanism of Action,Journal of Medicinal Chemistry

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N-Substituted 5-(1H-Indol-2-yl)-2-methoxyanilines Are Allosteric Inhibitors of the Linoleate Oxygenase Activity of Selected Mammalian ALOX15 Orthologs: Mechanism of Action
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-25 , DOI: 10.1021/acs.jmedchem.1c01563
Alexey Golovanov ₁ , Alexander Zhuravlev ₁ , Alejandro Cruz ₂ , Vladislav Aksenov ₁ , Rania Shafiullina ₁ , Kumar R Kakularam ₃ , José M Lluch _{2,

4} , Hartmut Kuhn ₃ , Àngels González-Lafont _{2,

4} , Igor Ivanov ₁

Affiliation

Here, we describe the first systematic study on the mechanism of substrate-selective inhibition of mammalian ALOX15 orthologs. For this purpose, we prepared a series of N-substituted 5-(1H-indol-2-yl)anilines and found that (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates and their monofluorinated analogues are potent and selective inhibitors of the linoleate oxygenase activity of rabbit and human ALOX15. Introduction of a 2-methoxyaniline moiety into the core pharmacophore plays a crucial role in substrate-selective inhibition of ALOX15-catalyzed oxygenation of linoleic acid at submicromolar concentrations without affecting arachidonic acid oxygenation. Steady-state kinetics, mutagenesis studies, and molecular dynamics (MD) simulations suggested an allosteric mechanism of action. Using a dimer model of ALOX15, our MD simulations suggest that the binding of the inhibitor at the active site of one monomer induces conformational alterations in the other monomer so that the formation of a productive enzyme–linoleic acid complex is energetically compromised.

中文翻译：

N-取代的 5-(1H-Indol-2-yl)-2-methoxyanilines 是选定哺乳动物 ALOX15 直系同源物亚油酸加氧酶活性的变构抑制剂：作用机制

在这里，我们描述了对哺乳动物 ALOX15 直系同源物的底物选择性抑制机制的首次系统研究。为此，我们制备了一系列N-取代的 5-(1 H -indol-2-yl)苯胺，发现 ( N -(5-(1 H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates 及其单氟化类似物是兔和人 ALOX15 亚油酸加氧酶活性的有效和选择性抑制剂。将 2-甲氧基苯胺部分引入核心药效团中在亚微摩尔浓度下选择性抑制 ALOX15 催化的亚油酸氧化而不影响花生四烯酸氧化中起关键作用。稳态动力学、诱变研究和分子动力学 (MD) 模拟表明了一种变构作用机制。使用 ALOX15 的二聚体模型，我们的 MD 模拟表明，抑制剂在一个单体的活性位点的结合诱导了另一个单体的构象改变，从而大大损害了生产性酶 - 亚油酸复合物的形成。

更新日期：2022-02-10

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