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Planta Med 2017; 83(11): 901-911
DOI: 10.1055/s-0043-104775
Natural Product Chemistry and Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Correlating In Vitro Target-Oriented Screening and Docking: Inhibition of Matrix Metalloproteinases Activities by Flavonoids[*] [#]

Lucia Crascì
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
,
Livia Basile
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
,
Annamaria Panico
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
,
Carmelo Puglia
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
,
Francesco P. Bonina
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
,
Pierluigi Maria Basile
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
,
Luisa Rizza
2   Bionap s. r. l., Contrada Fureria, Belpasso, Italy
,
Salvatore Guccione
1   Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy
› Author Affiliations
Further Information

Publication History

received 05 April 2016
revised 31 January 2017

accepted 17 February 2017

Publication Date:
13 March 2017 (online)

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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.

 

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