Molecular modelling study of the mechanism of high-potency inhibition of human catechol-O-methyltransferase by (-)-epigallocatechin-3-O-gallate

Xenobiotica. 2008 Feb;38(2):130-46. doi: 10.1080/00498250701744641.


The molecular mechanism of inhibition of human catechol-O-methyltransferase (COMT) by (-)-epigallocatechin-3-O-gallate (EGCG), which is a modest substrate of COMT but an ultra-potent inhibitor of this enzyme, was studied. EGCG has an IC(50) value of 70 nM for inhibiting human liver COMT-mediated O-methylation of 2-hydroxyestradiol, which was 210-760 times more potent than catechin, epigallocatechin and epicatechin. Kinetic analyses showed that EGCG had a strong component of non-competitive inhibition of the O-methylation of 2-hydroxyestradiol. Computational molecular modelling studies showed that the B- and D-rings of EGCG can bind tightly to the human COMT in four different modes (i.e. D-para-OH, D-meta-OH, B-para-OH, and B-meta-OH). The binding geometry of EGCG in these binding modes was found to be less than ideal to form perfect Mg(2+) coordination for the catalysis of its own methylation. It is concluded that the very tight binding interaction of EGCG with COMT makes it a potent non-competitive inhibitor, but its imperfect geometry makes it a poor substrate for methylation by this enzyme.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catechin / analogs & derivatives*
  • Catechin / chemistry
  • Catechin / pharmacology
  • Catechol O-Methyltransferase / chemistry*
  • Catechol O-Methyltransferase Inhibitors
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Kinetics
  • Methylation
  • Models, Molecular
  • Rats
  • Swine


  • Catechol O-Methyltransferase Inhibitors
  • Enzyme Inhibitors
  • Catechin
  • epigallocatechin gallate
  • Catechol O-Methyltransferase