INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity. Molecular mechanism and structureactivity relationship of the flavonoidenzyme interaction.
ALEJANDRA C SARAGUSTI; MARIA G ORTEGA; JOSE L CABRERA; DARIO A ESTRIN; MARCELO A MARTI; GUSTAVO A CHIABRANDO
EUROPEAN JOURNAL OF PHARMACOLOGY
ELSEVIER SCIENCE BV
Año: 2010 p. 138 - 138
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 structureactivityrelationship 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 structureactivityrelationship 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.