IMBIV   05474
INSTITUTO MULTIDISCIPLINARIO DE BIOLOGIA VEGETAL
Unidad Ejecutora - UE
artículos
Título:
Inhibitory effect of quercetin on the matrix metalloproteinase 9 activity. Molecular mechanism
Autor/es:
ALEJANDRA C. SARAGUSTI; MARÍA G. ORTEGA; JOSÉ L. CABRERA; DARÍO A. ESTRIN,; MARCELO A. MARTI,; GUSTAVO A. CHIABRANDO.
Revista:
EUROPEAN JOURNAL OF PHARMACOLOGY
Editorial:
ELSEVIER SCIENCE BV
Referencias:
Año: 2010 vol. 644 p. 146 - 153
ISSN:
0014-2999
Resumen:
Epidemiological studies suggest that the consumption of flavonoid-rich diets decreases the risk of cardiovascular diseases, but the protective mechanisms are not known. Increased activity of the matrix metalloproteinase 9 (MMP-9) has been implicated in the development and progression of atherosclerotic lesions. Herein we first evaluate the inhibitory effect of quercetin on the MMP-9 activity by fluorescent gelatin dequenching assay, secondly we determine the most probable sites and modes of quercetin interaction with the MMP-9 catalytic domain using a combination of docking and molecular dynamics (MD) simulation, and finally, we investigate the structural activity relationships (SARs) of the quercetin inhibition on the MMP-9 activity using quercetin structural analogs. We showed that quercetin inhibits the MMP-9 activity with an IC50 value of 22 ìM. Docking and MD simulation results revealed two most probable and stable quercetin-MMP-9 complex  structures where quercetin is stabilized in the S1´ subsite of the enzyme active site involving hydrogen bond interactions between quercetin hydroxyl substitutions and MMP-9 residues These data in combination with SARs demonstrate that the most relevant structural features of quercetin for the MMP-9 inhibition are: hydroxyl substitutions at R3´ and R4´, at least one hydroxyl substitution at R5 or R3, ortodihydroxilation on the B ring and 2,3-double bond conjugating A and B rings. Our data constitute the first evidence about a putative molecular mechanism of the inhibition of MMP-9 activity exerted by quercetin and some quercetin analogs, which could be used to explain the inhibitory effects of diet polyphenols on the MMP-9 activity.