Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction
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 les...
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todo:paper_00142999_v644_n1-3_p138_Saragusti2023-10-03T14:12:09Z Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction Saragusti, A.C. Ortega, M.G. Cabrera, J.L. Estrin, D.A. Marti, M.A. Chiabrando, G.A. Diet polyphenol Docking Flavonoid Molecular dynamics Zymography chrysin fisetin galangin gelatinase B kaempferol luteolin morin quercetin article binding site controlled study drug mechanism drug protein binding drug structure enzyme active site enzyme inhibition enzyme kinetics human human cell IC 50 molecular docking molecular dynamics priority journal structure activity relation structure analysis zymography Antioxidants Binding Sites Cell Line, Tumor Enzyme Inhibitors Flavonoids Humans Inhibitory Concentration 50 Matrix Metalloproteinase 9 Models, Molecular Protein Binding Quercetin Structure-Activity Relationship 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. © 2010 Elsevier B.V. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00142999_v644_n1-3_p138_Saragusti |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Diet polyphenol Docking Flavonoid Molecular dynamics Zymography chrysin fisetin galangin gelatinase B kaempferol luteolin morin quercetin article binding site controlled study drug mechanism drug protein binding drug structure enzyme active site enzyme inhibition enzyme kinetics human human cell IC 50 molecular docking molecular dynamics priority journal structure activity relation structure analysis zymography Antioxidants Binding Sites Cell Line, Tumor Enzyme Inhibitors Flavonoids Humans Inhibitory Concentration 50 Matrix Metalloproteinase 9 Models, Molecular Protein Binding Quercetin Structure-Activity Relationship |
| spellingShingle |
Diet polyphenol Docking Flavonoid Molecular dynamics Zymography chrysin fisetin galangin gelatinase B kaempferol luteolin morin quercetin article binding site controlled study drug mechanism drug protein binding drug structure enzyme active site enzyme inhibition enzyme kinetics human human cell IC 50 molecular docking molecular dynamics priority journal structure activity relation structure analysis zymography Antioxidants Binding Sites Cell Line, Tumor Enzyme Inhibitors Flavonoids Humans Inhibitory Concentration 50 Matrix Metalloproteinase 9 Models, Molecular Protein Binding Quercetin Structure-Activity Relationship Saragusti, A.C. Ortega, M.G. Cabrera, J.L. Estrin, D.A. Marti, M.A. Chiabrando, G.A. Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| topic_facet |
Diet polyphenol Docking Flavonoid Molecular dynamics Zymography chrysin fisetin galangin gelatinase B kaempferol luteolin morin quercetin article binding site controlled study drug mechanism drug protein binding drug structure enzyme active site enzyme inhibition enzyme kinetics human human cell IC 50 molecular docking molecular dynamics priority journal structure activity relation structure analysis zymography Antioxidants Binding Sites Cell Line, Tumor Enzyme Inhibitors Flavonoids Humans Inhibitory Concentration 50 Matrix Metalloproteinase 9 Models, Molecular Protein Binding Quercetin Structure-Activity Relationship |
| description |
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. © 2010 Elsevier B.V. |
| format |
JOUR |
| author |
Saragusti, A.C. Ortega, M.G. Cabrera, J.L. Estrin, D.A. Marti, M.A. Chiabrando, G.A. |
| author_facet |
Saragusti, A.C. Ortega, M.G. Cabrera, J.L. Estrin, D.A. Marti, M.A. Chiabrando, G.A. |
| author_sort |
Saragusti, A.C. |
| title |
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| title_short |
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| title_full |
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| title_fullStr |
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| title_full_unstemmed |
Inhibitory effect of quercetin on matrix metalloproteinase 9 activity Molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| title_sort |
inhibitory effect of quercetin on matrix metalloproteinase 9 activity molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction |
| url |
http://hdl.handle.net/20.500.12110/paper_00142999_v644_n1-3_p138_Saragusti |
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| _version_ |
1807322035338084352 |