215
becomes less flexible at the top which may reduce the affinity of the protein for the
indomethacin analogue, thereby accounting for its COX 2 selectivity. All structures
will not give an outlook into the mechanism of selectivity. Sulphonamide group of
NS-398 pairs ionically to Arg120. Similarly the crystallographic data of zomepiracderived COX 2 selective inhibitors do not provide a justification for their selective
COX 2 inhibition. The sulphonamide moiety of the inhibitor forms hydrogen bonds
with Arg120, Glu524 and Tyr355 in COX 2.
Crystal structure of COX was elucidated and new inhibitors were developed.
Based on the crystal structure, the active site binding and mode of inhibition were
studied in detail. COX1 structure was explained in 1994 and COX2 in 1996.
Several co-crystal compounds were reported in PDB these days which can be
developed into anti-inflammatory drugs. The crystal structure of sheep COX 1
complexed with an anti-inflammatory drug celecoxib was determined at 2.75 Å
(Fig.9.15). Residues Gln192 and Leu352 made hydrogen bonds with proteins and
ligands. A large number of van der Waal’s contacts are established with the residues His590, Ser516, Leu352, Ser353, Ile523, Phe518, Tyr355, Van349, Ala527
and Met522. This structure is deposited in PDB and available with the ID 3KK6
(Rimon et al. 2011).
NHSO2CH3
NHSO2CH3
NHSO2CH3
SO2CH3
SO2NH2
O
O
S
O
F
F
F
F
O
O
O
O
O
O
O
O
O
O
S
N
N
N
Na
C
N
N
N
N
N
S
S
O
O
OH
OH
CONH
H
C 2H5
C2H5
CH 2 CO 2 H
NHCOCH 3
OCH 2 H 5
NHCOCH 3
N
N
N
N
N
F3C
O
O
O
O
N
H
CH3
CH3
CH 3
CH3
CH3
CH3
CH3
CH3
H3C
H3C
H3C
CH3
CH3
NO2
H3C
S
S
O
F
Br
NO 2
NS398
Flosulide
DuP697
CGP28238
Rofecoxib
Amidopyrine
(aminopyrine)
Dipyrone
(Methampyrone)
Celecoxib
Nimesulide
Phenazone
(antipyrine)
Phenacetin
Paracetamol
c
b
a
Etodolac
Meloxicam
Fig. 9.14 Structure of NSAIDs: (a) Structures of DuP697, NS398 (b) isoform inhibitors (celecoxib and rofecoxib) and COX 2 selective inhibitors (meloxicam, etodolac and nimesulide) (c)
Effective COX-3 inhibitors
9 Anti-inflammatory Molecules: Enzyme Inhibitors
becomes less flexible at the top which may reduce the affinity of the protein for the
indomethacin analogue, thereby accounting for its COX 2 selectivity. All structures
will not give an outlook into the mechanism of selectivity. Sulphonamide group of
NS-398 pairs ionically to Arg120. Similarly the crystallographic data of zomepiracderived COX 2 selective inhibitors do not provide a justification for their selective
COX 2 inhibition. The sulphonamide moiety of the inhibitor forms hydrogen bonds
with Arg120, Glu524 and Tyr355 in COX 2.
Crystal structure of COX was elucidated and new inhibitors were developed.
Based on the crystal structure, the active site binding and mode of inhibition were
studied in detail. COX1 structure was explained in 1994 and COX2 in 1996.
Several co-crystal compounds were reported in PDB these days which can be
developed into anti-inflammatory drugs. The crystal structure of sheep COX 1
complexed with an anti-inflammatory drug celecoxib was determined at 2.75 Å
(Fig.9.15). Residues Gln192 and Leu352 made hydrogen bonds with proteins and
ligands. A large number of van der Waal’s contacts are established with the residues His590, Ser516, Leu352, Ser353, Ile523, Phe518, Tyr355, Van349, Ala527
and Met522. This structure is deposited in PDB and available with the ID 3KK6
(Rimon et al. 2011).
NHSO2CH3
NHSO2CH3
NHSO2CH3
SO2CH3
SO2NH2
O
O
S
O
F
F
F
F
O
O
O
O
O
O
O
O
O
O
S
N
N
N
Na
C
N
N
N
N
N
S
S
O
O
OH
OH
CONH
H
C 2H5
C2H5
CH 2 CO 2 H
NHCOCH 3
OCH 2 H 5
NHCOCH 3
N
N
N
N
N
F3C
O
O
O
O
N
H
CH3
CH3
CH 3
CH3
CH3
CH3
CH3
CH3
H3C
H3C
H3C
CH3
CH3
NO2
H3C
S
S
O
F
Br
NO 2
NS398
Flosulide
DuP697
CGP28238
Rofecoxib
Amidopyrine
(aminopyrine)
Dipyrone
(Methampyrone)
Celecoxib
Nimesulide
Phenazone
(antipyrine)
Phenacetin
Paracetamol
c
b
a
Etodolac
Meloxicam
Fig. 9.14 Structure of NSAIDs: (a) Structures of DuP697, NS398 (b) isoform inhibitors (celecoxib and rofecoxib) and COX 2 selective inhibitors (meloxicam, etodolac and nimesulide) (c)
Effective COX-3 inhibitors
9 Anti-inflammatory Molecules: Enzyme Inhibitors