Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure–activity relationship of the flavonoid–enzyme interaction

• Published in: European journal of pharmacology 2010-10, Vol.644 (1-3), p.138-145
• Main Authors: Saragusti, Alejandra C., Ortega, María G., Cabrera, José L., Estrin, Darío A., Marti, Marcelo A., Chiabrando, Gustavo A.
• Format: Article
• Language: English
• Subjects: Antioxidants - pharmacology; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Diet polyphenol; Docking; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Flavonoid; Flavonoids - chemistry; Flavonoids - pharmacology; Humans; Inhibitory Concentration 50; Matrix Metalloproteinase Inhibitors; Medical sciences; Models, Molecular; Molecular dynamics; Pharmacology. Drug treatments; Protein Binding; Quercetin - pharmacology; Structure-Activity Relationship; Zymography
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.07.001

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.