Subscribe to RSS
Download PDF
DOI: 10.1055/s-0043-104775
Correlating In Vitro Target-Oriented Screening and Docking: Inhibition of Matrix Metalloproteinases Activities by Flavonoids[*] [#]
Publication History
received 05 April 2016
revised 31 January 2017
accepted 17 February 2017
Publication Date:
13 March 2017 (online)
Abstract
Metalloproteases are a family of zinc-containing endopeptidases involved in a variety of pathological disorders. The use of flavonoid derivatives as potential metalloprotease inhibitors has recently increased.
Particular plants growing in Sicily are an excellent yielder of the flavonoids luteolin, apigenin, and their respective glycoside derivatives (7-O-rutinoside, 7-O-glucoside, and 7-O-glucuronide).
The inhibitory activity of luteolin, apigenin, and their respective glycoside derivatives on the metalloproteases MMP-1, MMP-3, MMP-13, MMP-8, and MMP-9 was assessed and rationalized correlating in vitro target-oriented screening and in silico docking.
The flavones apigenin, luteolin, and their respective glucosides have good ability to interact with metalloproteases and can also be lead compounds for further development. Glycones are more active on MMP-1, -3, -8, and -13 than MMP-9. Collagenases MMP-1, MMP-8, and MMP-13 are inhibited by compounds having rutinoside glycones. Apigenin and luteolin are inactive on MMP-1, -3, and -8, which can be interpreted as a better selectivity for both -9 and -13 peptidases. The more active compounds are apigenin-7-O-rutinoside on MMP-1 and luteolin-7-O-rutinoside on MMP-3. The lowest IC50 values were also found for apigenin-7-O-glucuronide, apigenin-7-O-rutinoside, and luteolin-7-O-glucuronide. The glycoside moiety might allow for a better anchoring to the active site of MMP-1, -3, -8, -9, and -13. Overall, the in silico data are substantially in agreement with the in vitro ones (fluorimetric assay).
Key words
Cynara cardunculus var. scolymus L. - Asteraceae - plant extracts - metalloprotease - flavonoids - glycosides* Dedicated to the memory of Carmela Spatafora.
# This work is part of the graduation thesis of P. M. B.
Supporting information
The representative dose-response curves for IC50 value determination of apigenin, luteolin, and their derivatives on all MMPs under study (Figs. S1–S9) are available as Supporting Information. The logarithmic values of each increasing micromolar (µM) concentration of the compounds are reported in the X-axes. The logarithm value of the 10−7 µM concentration (− 7) has been associated to a very low dose that gives the same response of “blank” (absence of the inhibitor). The increasing slope of the regression line value, which relates to a decrease in the inhibitory activity, is reported in the Y-axes. The values between the points were determined conducting a nonlinear fit using Origin software, version 7. The data obtained by Origin, version 7, were counterchecked by the GraphPad Prism software, version 7.00 [48], which was also used to obtain the graphs in Figs. S1–S9. For a better understanding of the graphs, a break in the X-axes, from the − 4 to − 6 logarithm values, was introduced. The dose-response curve of NNGH was used as a reference value for each determination.
-
References
- 1 Singh M, Kaur M, Silakari O. Favones: an important scaffold for medicinal chemistry. Eur J Med Chem 2014; 84: 206-239
- 2 Crascì L, Panico AM. Protective effects of many citrus flavonoids on cartilage degradation process. J Biomater Nanobiotechnol 2013; 4: 279-283
- 3 Merlo S, Basile L, Giuffrida ML, Sortino MA, Guccione S, Copani A. Identification of 5-methoxyflavone as a novel DNA polymerase-beta inhibitor and neuroprotective agent against beta-amyloid toxicity. J Nat Prod 2015; 78: 2704-2711
- 4 Lauro MR, Crascì L, Claudia C, Aquino RP, Panico AM, Puglisi G. Encapsulation of a citrus by-product extract: development, characterization and stability studies of a nutraceutical with antioxidant and metalloproteinases inhibitory activity. Food Sci Technol 2015; 62: 169-176
- 5 Matchett MD, MacKinnon SL, Sweeney MI, Gottschall-Pass KT, Hurta RA. Blueberry flavonoids inhibit matrix metalloproteinase activity in DU145 human prostate cancer cells. Biochem Cell Biol 2005; 83: 637-643
- 6 Mannello F. Natural bio-drugs as matrix metalloproteinase inhibitors: new perspectives on the horizon?. Recent Pat Anticancer Drug Discov 2006; 1: 91-103
- 7 Puglia C, Cardile V, Panico AM, Crascì L, Offerta A, Caggia S, Drechsler M, Mariani P, Cortesi R, Esposito E. Evaluation of monooleine aqueous dispersions as tools for topical administration of curcumin: characterization, in vitro and ex-vivo studies. J Pharm Sci 2013; 102: 2349-2361
- 8 Panico AM, Cardile V, Santagati NA, Messina R. Antioxidant and protective effects of Sumac leaves on chondrocytes. J Med Plants Res 2009; 3: 855-861
- 9 Tahanian E, Sanchez LA, Shiao TC, Roy R, Annabi B. Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells. Drug Des Devel Ther 2011; 5: 299-309
- 10 Craggs L, Kalaria RN. Revisiting dietary antioxidants, neurodegeneration and dementia. Neuroreport 2001; 22: 1-3
- 11 Panico AM, Cardile V, Avondo S, Garufi F, Gentile B, Puglia C, Bonina F, Santagati NA, Ronsisvalle G. The in vitro effect of a lyophilized extract of wine obtained from Jacquez grapes on human chondrocytes. Phytomedicine 2006; 13: 522-526
- 12 Sim GS, Lee BC, Cho HS, Lee JW, Kim JH, Lee DH, Kim JH, Pyo HB, Moon DC, Oh KW, Yun YP, Hong JT. Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVA-irradiated human dermal fibroblast. Arch Pharm Res 2007; 30: 290-298
- 13 Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Woźniak K, Nabavi SM. Luteolin as an anti-inflammatory and neuroprotective agent: A brief review. Brain Res Bull 2015; 119: 1-11
- 14 Breiter T, Laue C, Kressel G, Gröll S, Engelhardt UH, Hahn A. Bioavailability and antioxidant potential of rooibos flavonoids in humans following the consumption of different rooibos formulations. Food Chem 2011; 128: 338-347
- 15 Jones GT. Matrix metalloproteinases in biologic samples. Adv Clin Chem 2014; 65: 199-219
- 16 Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 2013; 21: 16-21
- 17 Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res 2006; 69: 614-624
- 18 Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 2006; 11: 1696-1701
- 19 Coussens LM, Werb Z. Inflammation and cancer. Nature 2012; 420: 860-867
- 20 Wang S, Moustaid-Moussa N, Chen L, Mo H, Shastri A, Su R, Bapat P, Kwun I, Shen CL. Novel insights of dietary polyphenols and obesity. J Nutr Biochem 2014; 25: 1-18
- 21 Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm 2013; 2013: 928315
- 22 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874
- 23 Nissinen L, Kähäri VM. Matrix metalloproteinases in inflammation. Biochim Biophys Acta 2014; 1840: 2571-2580
- 24 Mittal B, Mishra A, Srivastava A, Kumar S, Garg N. Matrix metalloproteinases in coronary artery disease. Adv Clin Chem 2014; 64: 1-72
- 25 Kaczmarek L. Mmp-9 inhibitors in the brain: can old bullets shoot new targets?. Curr Pharm Des 2013; 19: 1085-1089
- 26 Nalivaeva NN, Fisk LR, Belyaev ND, Turner AJ. Amyloid-degrading enzymes as therapeutic targets in Alzheimerʼs disease. Curr Alzheimer Res 2008; 5: 212-224
- 27 Sartor L, Pezzato E, DellʼAica I, Caniato R, Biggin S, Garbisa S. Inhibition of matrix-proteases by polyphenols: chemical insights for anti-inflammatory and anti-invasion drug design. Biochem Pharmacol 2002; 64: 229-237
- 28 Saragutzi AC, Ortega MG, Cabrera JL, Estrin DA, Marti MA, Chiabrando GA. Inhibitory effect of quercetin on matrix metalloproteinase 9 activity molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. Eur J Pharmacol 2010; 644: 138-145
- 29 Ende C, Gebhardt R. Inhibition of matrix metalloproteinase-2 and -9 activities by selected flavonoids. Planta Med 2004; 70: 1006-1008
- 30 Lim H, Hyun PK. Inhibition of mammalian collagenase, matrix metalloproteinase-1, by naturally-occurring flavonoids. Planta Med 2007; 73: 1267-1274
- 31 Bellosta S, Bogani P, Canavesi M, Galli C, Visioli F. Mediterranean diet and cardioprotection: wild artichoke inhibits metalloproteinase 9. Mol Nutr Food Res 2008; 52: 1147-1152
- 32 Zhang J, Li H, Zhou X, Fan YR, Zhou ZG, Yaoc QZ. Computational studies on structural modifications for the inhibition of matrix metalloproteinase activities by luteolin. Can J Chem 2013; 91: 1009-1017
- 33 Ge H, Liu J, Zhao W, Wang Y, He Q, Wu R, Li D, Xu J. Mechanistic studies for tri-targeted inhibition of enzymes involved in cholesterol biosynthesis by green tea polyphenols. Org Biomol Chem 2014; 12: 4941-4951
- 34 Houlton S. Chemistry in bloom. Chemistry World. October 2014, 46. Available at http://www.chemistryworld.org Accessed March 7, 2017
- 35 Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wähälä K, Montesano R, Schweigerer L. Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res 1997; 57: 2916-2921
- 36 Shukla S, Gupta S. Apigenin: a promising molecule for cancer prevention. Pharm Res 2010; 27: 962-978
- 37 Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potentials for cancer prevention and therapy. Curr Cancer Drug Targets 2008; 8: 634-646
- 38 Klebe G. Applying thermodynamic profiling in lead finding and optimization. Nat Rev Drug Discov 2015; 14: 95-110
- 39 Biela A, Sielaff F, Terwesten F, Heine A, Steinmetzer T, Klebe G. Ligand binding stepwise disrupts water network in thrombin: enthalpic and entropic changes reveal classical hydrophobic effect. J Med Chem 2012; 55: 6094-6110
- 40 Nasief NN, Tan H, Kong J, Hangauer D. Water mediated ligand functional group cooperativity: the contribution of a methyl group to binding affinity is enhanced by a COO(−) group through changes in the structure and thermodynamics of the hydration waters of ligand-thermolysin complexes. J Med Chem 2012; 55: 8283-8302
- 41 Origin version 7. OriginLab Corporation. Available at http://www.originlab.com
- 42 Bertini I, Calderone V, Fragai M, Giachetti A, Loconte M, Luchinat C, Maletta M, Nativi C, Yeo KJ. Exploring the subtleties of drug-receptor interactions: the case of matrix metalloproteinases. J Am Chem Soc 2007; 129: 2466-2475
- 43 Alcaraz LA, Banci L, Bertini I, Cantini F, Donaire A, Gonnelli L. Matrix metalloproteinase – inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors. J Biol Inorg Chem 2007; 12: 1197-1206
- 44 Thomsen R, Christensen MH. MolDock: a new technique for high-accuracy molecular docking. J Med Chem 2006; 49: 3315-3321
- 45 Bode W, Maskos K. Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biol Chem 2003; 384: 863-872
- 46 Sybyl-X, Tripos (A CertaraCompany). Available at http://www.tripos.com
- 47 The Protein Data Bank. Available at http://www.rcsb.org/pdb
- 48 Prism version 7.00, GraphPad software. Available at http://www.graphpad.com