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

Autor: Golovanov A; Lomonosov Institute of Fine Chemical Technologies, MIREA─Russian Technological University, Vernadskogo Pr. 86, 119571 Moscow, Russia., Zhuravlev A; Lomonosov Institute of Fine Chemical Technologies, MIREA─Russian Technological University, Vernadskogo Pr. 86, 119571 Moscow, Russia., Cruz A; Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain., Aksenov V; Lomonosov Institute of Fine Chemical Technologies, MIREA─Russian Technological University, Vernadskogo Pr. 86, 119571 Moscow, Russia., Shafiullina R; Lomonosov Institute of Fine Chemical Technologies, MIREA─Russian Technological University, Vernadskogo Pr. 86, 119571 Moscow, Russia., Kakularam KR; Department of Biochemistry, Charite─University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, D-10117 Berlin, Germany., Lluch JM; Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.; Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain., Kuhn H; Department of Biochemistry, Charite─University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, D-10117 Berlin, Germany., González-Lafont À; Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.; Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain., Ivanov I; Lomonosov Institute of Fine Chemical Technologies, MIREA─Russian Technological University, Vernadskogo Pr. 86, 119571 Moscow, Russia.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 1979-1995. Date of Electronic Publication: 2022 Jan 25.
DOI: 10.1021/acs.jmedchem.1c01563
Abstrakt: 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-(1 H -indol-2-yl)anilines and found that ( N -(5-(1 H -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.
Databáze: MEDLINE
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