Interaction between quercetin and metalloproteinases art the active site as a mechanism for enzime inhibition

ALEJANDRA SARAGUSTI; GABRIELA ORTEGA; MARCELO MARTI; DARIO ESTRIN; JOSE LUIS CABRERA; GUSTAVO CHIABRANDO

Salamanca, España

Conferencia; XXIV International Conference on Polyphenols; 2008

  Among others polyphenols, quercetin is one of the most commonly flavonoid found in human diet. Increased activity of matrix metalloproteinases (MMPs) has been implicated in the development and progression of atherosclerotic lesions, especially the gelatinase MMP-9. Although it has been reported the inhibitory effect of certain polyphenols on MMP activity, the molecular mechanisms of this inhibition are still unknown. Herein we first evaluate the inhibitory effect of quercetin on the active MMP-9 by zimography assays and secondly we determine the most probable sites of quercetin interaction with the MMP-9 catalytic domain using a combination of docking techniques and molecular dynamics (MD) simulations. By zymography assays we showed that this flavonoid inhibits the enzyme activity in a dose and time dependent manner with an IC50 of 54.0 ± 3.3 ìM. In  addition, the evaluation of possible interaction sites between quercetin and MMP-9 demonstrated that quercetin may bind to different subsites of the enzyme active site. The results revealed five possible quercetin-MMP-9 complex structures where quercetin is stabilized in the MMP-9 active site by hydrophobic interactions and hydrogen bonds involving flavonoid hydroxyls and enzyme residues.