化学
变构调节
立体化学
部分
药效团
花生四烯酸
酶
加氧酶
基质(水族馆)
作用机理
单体
突变
生物化学
有机化学
突变
基因
体外
聚合物
地质学
海洋学
作者
A. B. Golovanov,А. В. Журавлев,Alejandro Cruz,Vladislav Aksenov,Rania Shafiullina,Kumar Reddy Kakularam,José M. Lluch,Hartmut Kühn,Àngels González‐Lafont,Igor Ivanov
标识
DOI:10.1021/acs.jmedchem.1c01563
摘要
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.
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