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Different Structures-Similar Effect: Do Substituted 5-(4-Methoxyphenyl)-1 H -indoles and 5-(4-Methoxyphenyl)-1 H -imidazoles Represent a Common Pharmacophore for Substrate Selective Inhibition of Linoleate Oxygenase Activity of ALOX15?

التفاصيل البيبلوغرافية
العنوان: Different Structures-Similar Effect: Do Substituted 5-(4-Methoxyphenyl)-1 H -indoles and 5-(4-Methoxyphenyl)-1 H -imidazoles Represent a Common Pharmacophore for Substrate Selective Inhibition of Linoleate Oxygenase Activity of ALOX15?
المؤلفون: 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, Bellaterra, 08193 Barcelona, Spain., Aksenov V; Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, Vernadskogo pr. 86, 119571 Moscow, Russia.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklihio-Maklaja Str., 16/10c4, 117997 Moscow, Russia., Golovanov A; Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, Vernadskogo pr. 86, 119571 Moscow, Russia., Lluch JM; Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.; Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain., Kuhn H; Department of Biochemistry, Charite-University Medicine Berlin, Corporate Member of Free University Berlin and Humboldt University Berlin, Charitéplatz 1, D-10117 Berlin, Germany., González-Lafont À; Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.; Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain., Ivanov I; Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, Vernadskogo pr. 86, 119571 Moscow, Russia.
المصدر: Molecules (Basel, Switzerland) [Molecules] 2023 Jul 14; Vol. 28 (14). Date of Electronic Publication: 2023 Jul 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c1995-
مواضيع طبية MeSH: Linoleic Acid*/metabolism , Pharmacophore*, Animals ; Rabbits ; Mammals/metabolism ; Linoleic Acids/metabolism ; Arachidonate 15-Lipoxygenase/chemistry ; Imidazoles/pharmacology ; Imidazoles/metabolism
مستخلص: Mammalian 15-lipoxygenases (ALOX15) are lipid peroxidizing enzymes that exhibit variable functionality in different cancer and inflammation models. The pathophysiological role of linoleic acid- and arachidonic acid-derived ALOX15 metabolites rendered this enzyme a target for pharmacological research. Several indole and imidazole derivatives inhibit the catalytic activity of rabbit ALOX15 in a substrate-specific manner, but the molecular basis for this allosteric inhibition remains unclear. Here, we attempt to define a common pharmacophore, which is critical for this allosteric inhibition. We found that substituted imidazoles induce weaker inhibitory effects when compared with the indole derivatives. In silico docking studies and molecular dynamics simulations using a dimeric allosteric enzyme model, in which the inhibitor occupies the substrate-binding pocket of one monomer, whereas the substrate fatty acid is bound at the catalytic center of another monomer within the ALOX15 dimer, indicated that chemical modification of the core pharmacophore alters the enzyme-inhibitor interactions, inducing a reduced inhibitory potency. In our dimeric ALOX15 model, the structural differences induced by inhibitor binding are translated to the hydrophobic dimerization cluster and affect the structures of enzyme-substrate complexes. These data are of particular importance since substrate-specific inhibition may contribute to elucidation of the putative roles of ALOX15 metabolites derived from different polyunsaturated fatty acids in mammalian pathophysiology.
Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study or in the decision to publish the results.
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معلومات مُعتمدة: FSFZ-2023-0004 Russian Ministry of Science and High Education; PID2020-113764GB-I00 Spanish "Ministerio de Ciencia, Innovación y Universidades
فهرسة مساهمة: Keywords: allosteric inhibition; eicosanoids; lipoxygenase inhibitors; molecular dynamics; protein–protein interactions
المشرفين على المادة: 9KJL21T0QJ (Linoleic Acid)
0 (Linoleic Acids)
EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
0 (Imidazoles)
تواريخ الأحداث: Date Created: 20230729 Date Completed: 20230731 Latest Revision: 20230801
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10383952
DOI: 10.3390/molecules28145418
PMID: 37513289
قاعدة البيانات: MEDLINE
الوصف
تدمد:1420-3049
DOI:10.3390/molecules28145418