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
Golovanov, Alexey (Russian Technological University. Lomonosov Institute of Fine Chemical Technologies)
Zhuravlev, Alexander (Russian Technological University. Lomonosov Institute of Fine Chemical Technologies)
Cruz, Alejandro (Universitat Autònoma de Barcelona. Departament de Química)
Aksenov, Vladislav (Russian Technological University. Lomonosov Institute of Fine Chemical Technologies)
Shafiullina, Rania (Russian Technological University. Lomonosov Institute of Fine Chemical Technologies)
Kakularam, Kumar R. (University Medicine Berlin. Department of Biochemistry, Charité)
Lluch López, Josep Maria (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Kuhn, Hartmut (University Medicine Berlin. Department of Biochemistry, Charité)
González-Lafont, Àngels (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Ivanov, Igor (Russian Technological University. Lomonosov Institute of Fine Chemical Technologies)

Data:	2022
Resum:	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.
Ajuts:	Agencia Estatal de Investigación CTQ2017-83745-P
Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	5-(1H-indol-2-yl)-2-methoxyanilines ; Lipoxygenase inhibitors ; Allosterism ; Protein-protein interactions ; Molecular dynamics
Publicat a:	Journal of Medicinal Chemistry, Vol. 65, Issue 3 (February 2022) , p. 1979-1995, ISSN 1520-4804

DOI: 10.1021/acs.jmedchem.1c01563
PMID: 35073698

Postprint 29 p, 3.4 MB

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