208
Another series of indole-3- glyoxamide derivatives were developed which have
higher potency than acetamide (Snyder et al. 1999).
Another class of inhibitors was developed based on the derivatization of
D-tyrosine. Structure of benzyl derivative of tyrosine co-crystallized with human
PLA 2 revealed the presence of hydrogen bond through amide NH group to His48,
multiple hydrophobic interaction and a T-shaped aromatic group His interaction
along with metal-chelating carboxylate and amide oxygen atom (Hansford et al.
2003).
9.2.1.4 Natural Inhibitors of PLA 2
PLA 2 inhibitors were isolated from plants, microorganisms and marine-associated
organisms. Aristolochia sp., used in traditional medicines for snakebites, contains
Aristolochic acid which significantly inhibited PLA 2 . Other naturally derived flavonoid compounds, including rutin and quercetin, also have inhibitory effect.
Coumarin derivatives isolated from Eclipta alba, Ellagic acid, 3,3′-di-O-methyl
ellagic acid, 3′-O-methyl ellagic acid, 3-O-methyl-3,4′-methylenedioxy ellagic acid
from Casearia sylvestris SW (Flacourtiaceae), 2- hydroxy −4-methoxy benzoic
acid from Hemidesmus indicus root extract and Rosmarinic acid from Cordia verbenacea were found to be inhibitors of PLA 2 . Marine sources are also potent inhibitors of PLA 2 . The first isolated compound manolide (IC 50− 7.5 μm) (Mayer 1989)
and other compounds including ircinin (Cholbi et al. 1996), variabilin (IC 50− 6.9
μM) (Escrig et al. 1997) and petrosaspongiolide M (Garcia-Pastor et al. 1999)
inhibited PLA 2 .
An isoquinoline alkaloid berberine (Chandra et al. 2011) from Cardiospermum
halicacabum when complexed with Russell Viper venom phospholipase A 2 gave
crystal diffracting at a resolution of 1.93 Å showed in two hydrogen bonds by Gly30
and His48, one direct and the other water mediated which were formed between
berberine and the enzyme (Chandra et al. 2011). Hydrophobic interaction was found
between the hydrophobic surfaces of berberine and hydrophobic contacts with side
chains of neighbouring amino acids. The bio-transformed berberine also has a better
PLA 2 inhibition and its co-crystal structure has a resolution of 2.4 Å. Structural
details proved that insertion of dihydroxy-berberine in an identical orientation to
that of berberine causes an immediate increase in negative electron density. This
proves that dihydroxy-berberine binds in an inverted orientation with respect to
native berberine. This is corroborative to the results of in silico molecular docking
studies conducted earlier (Fig. 9.7).
Another study revealed that catechol, (1,2-dihydroxybenzene) naturally occurring polyphenol, binds at the active site cleft opening (Dileep et al. 2011) (Fig. 9.8).
This inhibition nature of catechol can be explored for its use as an anti- inflammatory
agent. The enzyme kinetics study of n-hexadecanoic acid (Aparna et al. 2012)
proved that it can also inhibit PLA 2 in a competitive manner. Crystal structure of
n-hexadecanoic acid with PLA 2 obtained at 2.5 Å resolution is shown in Fig. 9.8.
The binding constant and binding energy were calculated, and the results from the
structural and kinetics studies reported that the fatty acid, n-hexadecanoic acid, is an
inhibitor of PLA 2 (Aparna et al. 2012) . The presence of this anti-inflammatory
C.S. Sharanya and M. Haridas
Another series of indole-3- glyoxamide derivatives were developed which have
higher potency than acetamide (Snyder et al. 1999).
Another class of inhibitors was developed based on the derivatization of
D-tyrosine. Structure of benzyl derivative of tyrosine co-crystallized with human
PLA 2 revealed the presence of hydrogen bond through amide NH group to His48,
multiple hydrophobic interaction and a T-shaped aromatic group His interaction
along with metal-chelating carboxylate and amide oxygen atom (Hansford et al.
2003).
9.2.1.4 Natural Inhibitors of PLA 2
PLA 2 inhibitors were isolated from plants, microorganisms and marine-associated
organisms. Aristolochia sp., used in traditional medicines for snakebites, contains
Aristolochic acid which significantly inhibited PLA 2 . Other naturally derived flavonoid compounds, including rutin and quercetin, also have inhibitory effect.
Coumarin derivatives isolated from Eclipta alba, Ellagic acid, 3,3′-di-O-methyl
ellagic acid, 3′-O-methyl ellagic acid, 3-O-methyl-3,4′-methylenedioxy ellagic acid
from Casearia sylvestris SW (Flacourtiaceae), 2- hydroxy −4-methoxy benzoic
acid from Hemidesmus indicus root extract and Rosmarinic acid from Cordia verbenacea were found to be inhibitors of PLA 2 . Marine sources are also potent inhibitors of PLA 2 . The first isolated compound manolide (IC 50− 7.5 μm) (Mayer 1989)
and other compounds including ircinin (Cholbi et al. 1996), variabilin (IC 50− 6.9
μM) (Escrig et al. 1997) and petrosaspongiolide M (Garcia-Pastor et al. 1999)
inhibited PLA 2 .
An isoquinoline alkaloid berberine (Chandra et al. 2011) from Cardiospermum
halicacabum when complexed with Russell Viper venom phospholipase A 2 gave
crystal diffracting at a resolution of 1.93 Å showed in two hydrogen bonds by Gly30
and His48, one direct and the other water mediated which were formed between
berberine and the enzyme (Chandra et al. 2011). Hydrophobic interaction was found
between the hydrophobic surfaces of berberine and hydrophobic contacts with side
chains of neighbouring amino acids. The bio-transformed berberine also has a better
PLA 2 inhibition and its co-crystal structure has a resolution of 2.4 Å. Structural
details proved that insertion of dihydroxy-berberine in an identical orientation to
that of berberine causes an immediate increase in negative electron density. This
proves that dihydroxy-berberine binds in an inverted orientation with respect to
native berberine. This is corroborative to the results of in silico molecular docking
studies conducted earlier (Fig. 9.7).
Another study revealed that catechol, (1,2-dihydroxybenzene) naturally occurring polyphenol, binds at the active site cleft opening (Dileep et al. 2011) (Fig. 9.8).
This inhibition nature of catechol can be explored for its use as an anti- inflammatory
agent. The enzyme kinetics study of n-hexadecanoic acid (Aparna et al. 2012)
proved that it can also inhibit PLA 2 in a competitive manner. Crystal structure of
n-hexadecanoic acid with PLA 2 obtained at 2.5 Å resolution is shown in Fig. 9.8.
The binding constant and binding energy were calculated, and the results from the
structural and kinetics studies reported that the fatty acid, n-hexadecanoic acid, is an
inhibitor of PLA 2 (Aparna et al. 2012) . The presence of this anti-inflammatory
C.S. Sharanya and M. Haridas