Inhibition of Cyclooxygenase by Blocking the Reducing Cosubstrate at the
peroxidase site: Discovery of Galangin as a Novel Cyclooxygenase
Inhibitor
Abstract
Earlier we have shown that certain flavonoids (e.g., quercetin and
myricetin) are high-affinity reducing cosubstrates for cyclooxygenase 1
and 2 (COX-1 and COX-2). These compounds can bind inside the peroxidase
active site of COX-1 and COX-2 and donate an electron from one of their
B-ring hydroxyl groups to hematin. Based on these earlier findings, it
is speculated that some of the natural flavonoids that are structural
analogs of quercetin but lack the proper B-ring hydroxyl groups might
function as novel inhibitors of COX enzymes by blocking the effect of
the reducing cosubstrates. This idea is tested in the present study.
Computational docking analysis together with quantum chemistry
calculation shows that galangin, which shares the same overall structure
as quercetin but does not have any hydroxyl group in its B-ring, can
bind inside the peroxidase active sites of COX-1 and COX-2 in a similar
manner as quercetin, but it has little ability to effectively donate its
electrons, thereby blocking the effect of the reducing cosubstrates like
quercetin. Further experimental studies confirm that galangin can
inhibit, both in vitro and in vivo, quercetin-mediated activation of the
peroxidase activity of COX-1 and COX-2. The results of this study
demonstrate that galangin is a novel naturally-occurring inhibitor of
COX-1 and COX-2, acting by blocking the function of the reducing
cosubstrates at the peroxidase sites.