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Abstract:

Epidemiological studies have demonstrated an inverse association between the consumption of flavonoid-rich diets and the risk of atherosclerosis. In addition, an increased activity of the matrix metalloproteinase 9 (MMP-9) has been implicated in the development and progression of atherosclerotic lesions. Even though the relationship between flavonoid chemical structure and the inhibitory property on MMP activity has been established, the molecular mechanisms of this inhibition are still unknown. Herein, we first evaluated the inhibitory effect of quercetin on MMP-9 activity by zymography and a fluorescent gelatin dequenching assay, secondly we determined the most probable sites and modes of quercetin interaction with the MMP-9 catalytic domain by using molecular modelling techniques, and finally, we investigated the structure-activity relationship of the inhibitory effect of flavonoids on MMP-9 activity. We show that quercetin inhibited MMP-9 activity with an IC50 value of 22μM. By using docking and molecular dynamics simulations, it was shown that quercetin interacted in the S1' subsite of the MMP-9 active site. Moreover, the structure-activity relationship analysis demonstrated that flavonoid R3'-OH and R4'-OH substitutions were relevant to the inhibitory property against MMP-9 activity. In conclusion, our data constitute the first evidence about the quercetin and MMP-9 interaction, suggesting a mechanism to explain the inhibitory effect of the flavonoid on the enzymatic activity of MMP-9, which provides an additional molecular target for the cardioprotective activity of quercetin. © 2010 Elsevier B.V.

Registro:

Documento: Artículo
Título:Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction
Autor:Saragusti, A.C.; Ortega, M.G.; Cabrera, J.L.; Estrin, D.A.; Marti, M.A.; Chiabrando, G.A.
Filiación:Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Instituto Multidisciplinario de Biología Vegetal (IMBIV), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Instituto de Química-Física de Materiales, Medio Ambiente y Energía (INQUIMAE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Departamento de Bioquímica Clínica, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria (5000), Córdoba, Argentina
Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria (5000), Córdoba, Argentina
Departamento de Química Inorgánica, Analítica y Química Física, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, C1428EHA) Ciudad de Buenos Aires, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II,(C1428EHA) Ciudad de Buenos Aires, Argentina
INQUIMAE-CONICET, Ciudad Universitaria, Pabellón II, (C1428EHA) Ciudad de Buenos Aires, Argentina
Palabras clave:Diet polyphenol; Docking; Flavonoid; Molecular dynamics; Zymography; chrysin; fisetin; galangin; gelatinase B; kaempferol; luteolin; morin; quercetin; article; binding site; controlled study; drug mechanism; drug protein binding; drug structure; enzyme active site; enzyme inhibition; enzyme kinetics; human; human cell; IC 50; molecular docking; molecular dynamics; priority journal; structure activity relation; structure analysis; zymography; Antioxidants; Binding Sites; Cell Line, Tumor; Enzyme Inhibitors; Flavonoids; Humans; Inhibitory Concentration 50; Matrix Metalloproteinase 9; Models, Molecular; Protein Binding; Quercetin; Structure-Activity Relationship
Año:2010
Volumen:644
Número:1-3
Página de inicio:138
Página de fin:145
DOI: http://dx.doi.org/10.1016/j.ejphar.2010.07.001
Título revista:European Journal of Pharmacology
Título revista abreviado:Eur. J. Pharmacol.
ISSN:00142999
CODEN:EJPHA
CAS:chrysin, 12624-02-1, 480-40-0; fisetin, 528-48-3; galangin, 548-83-4; gelatinase B, 146480-36-6; kaempferol, 520-18-3; luteolin, 491-70-3; morin, 480-16-0; quercetin, 117-39-5; Antioxidants; Enzyme Inhibitors; Flavonoids; Matrix Metalloproteinase 9, 3.4.24.35; Quercetin, 117-39-5
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v644_n1-3_p138_Saragusti

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Citas:

---------- APA ----------
Saragusti, A.C., Ortega, M.G., Cabrera, J.L., Estrin, D.A., Marti, M.A. & Chiabrando, G.A. (2010) . Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. European Journal of Pharmacology, 644(1-3), 138-145.
http://dx.doi.org/10.1016/j.ejphar.2010.07.001
---------- CHICAGO ----------
Saragusti, A.C., Ortega, M.G., Cabrera, J.L., Estrin, D.A., Marti, M.A., Chiabrando, G.A. "Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction" . European Journal of Pharmacology 644, no. 1-3 (2010) : 138-145.
http://dx.doi.org/10.1016/j.ejphar.2010.07.001
---------- MLA ----------
Saragusti, A.C., Ortega, M.G., Cabrera, J.L., Estrin, D.A., Marti, M.A., Chiabrando, G.A. "Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction" . European Journal of Pharmacology, vol. 644, no. 1-3, 2010, pp. 138-145.
http://dx.doi.org/10.1016/j.ejphar.2010.07.001
---------- VANCOUVER ----------
Saragusti, A.C., Ortega, M.G., Cabrera, J.L., Estrin, D.A., Marti, M.A., Chiabrando, G.A. Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. Eur. J. Pharmacol. 2010;644(1-3):138-145.
http://dx.doi.org/10.1016/j.ejphar.2010.07.001