INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
artículos
Título:
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity. Molecular mechanism and structure–activity relationship of the flavonoid–enzyme interaction.
Autor/es:
ALEJANDRA C SARAGUSTI; MARIA G ORTEGA; JOSE L CABRERA; DARIO A ESTRIN; MARCELO A MARTI; GUSTAVO A CHIABRANDO
Revista:
EUROPEAN JOURNAL OF PHARMACOLOGY
Editorial:
ELSEVIER SCIENCE BV
Referencias:
Año: 2010 p. 138 - 138
ISSN:
0014-2999
Resumen:
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 thoughthe relationship between flavonoid chemical structure and the inhibitory property on MMP activity has beenestablished, the molecular mechanisms of this inhibition are still unknown. Herein, we first evaluated theinhibitory 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-9catalytic domain by using molecular modelling techniques, and finally, we investigated the structure–activityrelationship of the inhibitory effect of flavonoids on MMP-9 activity. We show that quercetin inhibited MMP-9 activity with an IC50 value of 22 μM. By using docking and molecular dynamics simulations, it was shownthat quercetin interacted in the S1′ subsite of the MMP-9 active site. Moreover, the structure–activityrelationship analysis demonstrated that flavonoid R3′–OH and R4′–OH substitutions were relevant to theinhibitory property against MMP-9 activity. In conclusion, our data constitute the first evidence about thequercetin and MMP-9 interaction, suggesting a mechanism to explain the inhibitory effect of the flavonoidon the enzymatic activity of MMP-9, which provides an additional molecular target for the cardioprotectiveactivity of quercetin.