Direct inhibition of matrix metalloproteinase-2 (MMP-2) by (−)-epigallocatechin-3-gallate: A possible role for the fibronectin type II repeats

• This in silico study addresses EGCG-mediated inhibition of MMP-2.
• EGCG targets the fibronectin type II repeats 1 and 3.
• It interacts with residues in the vicinity of the exosite of this enzyme.
• It hinders proper positioning of the substrate in the active site.
• The study offers a novel lead towards development of MMP-2 specific inhibitors.

Matrix metalloproteinases (MMPs) -2 and -9, also called gelatinases, constitute a distinct subgroup within the MMP family of extracellular matrix remodeling proteases. Gelatinases are implicated in tumor cell invasion and metastasis, and are attractive therapeutic targets. Several synthetic small molecule inhibitors of MMPs developed till date have failed in clinical trials. This has prompted explorations into the gamut of dietary compounds and nutraceuticals for specific inhibitors of MMPs with desirable properties. (−)-epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, is popular as a potential chemotherapeutic agent with demonstrable anti-metastatic and MMP inhibitory activities. Here, we have addressed the mechanism of EGCG-mediated inhibition of MMP-2 using in silico molecular docking approach. We show for the first time that EGCG targets the fibronectin type II repeat regions 1 and 3 of MMP-2, binds amino acids that constitute the exosite of this enzyme and hinders proper positioning of the substrate. This study offers a novel insight into the inhibition of MMP-2 by EGCG and presents a starting point for development of novel therapeutic molecules that can specifically target the gelatinases.