Cyclooxygenase (
COX) is a key enzyme in the biosynthetic path
way leading to the formation of prostaglandins,
which are mediators of inflammation [D.L. De
witt, W.L. Smith, Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence, Proc. Natl. Acad. Sci. USA 85 (1988) 1412–1416,
1]. It exists mainly in t
wo isoforms COX-1 and COX-2 [A. Raz, A. Wyche, N. Siegel, P. Needleman, Regulation of fibroblast cyclooxygenase synthesis by interleukin-1, J. Biol. Chem. 263 (1988) 3022–3028,
2]. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) have adverse gastrointestinal side-effects, because they inhibit both isoforms [T.D. Warner, F. Guiliano, I. Vojnovic, A. Bukasa, J.A.
Mitchell, J.P. Vane, Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated
with human gastrointestinal toxicity: a full in vitro analysis, Proc. Natl. Acad. Sci. USA 96 (1999) 7563–7568,
3; L.J. Marnett, A.S. Kalgutkar, Cyclooxygenase 2 inhibitors: discovery, selectivity and the future, Trends Pharmacol. Sci. 20 (1999) 465–469,
4; J.R. Vane, NSAIDs, Cox-2 inhibitors, and the gut, Lancet 346 (1995) 1105–1106,
5]. Therefore drugs
which selectively inhibit COX-2, kno
wn as
coxibs
were developed. Recent reports on the harmful cardiovascular and renovascular side-effects of the anti-inflammatory drugs have led to the quest for a novel class of COX-2 selective inhibitors. Keeping this in mind,
we have used the X-ray crystal structures of the complexes of the COX-1 and COX-2
with the kno
wn inhibitors for a rational, structure based approach to design a small peptide,
which is potent inhibitor for COX-2. The peptides have been checked experimentally by in-vitro kinetic studies using surface plasmon resonance (SPR) and other biochemical methods. We have identified a tripeptide inhibitor
which is a potential lead for a ne
w class of COX-2 inhibitor. The dissociation constant (
KD) determined for COX-2
with peptide WCS is 1.90 × 10
−10 M, the kinetic constant (
Ki) determined by spectrophotometry is 4.85 × 10
−9 M and the IC
50 value is 1.5 × 10
−8 M by ELISA test.