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January 11, 2003 B.M.S. College of Engineering
Uday Maitra
Department of Organic Chemistry
Indian Institute of Science
Bangalore 560 012
Email: [email protected]
Common enzyme-inhibiting Drugs
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NH2
R
COOH
NH2
NH
NH
NH
NH
NH
O
O
O
OA
B D
E
O
20 common amino acids
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Enzymes have immense catalytic power
(but they cannot alter reaction equilibria)Enzymes are highly specific
The catalytic activities of many enzymes are highly regulated
Enzymes accelerate reactions by stabilizing transition states
For example, 1 molecule of carbonic anhydrase
carries out the following reaction
on 100,000 molecules of CO2per second
CO2 + H2O = HCO3- + H+
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Competitive inhibition
Non-competitive inhibition
V = Vmax [S/(S + Km)]
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Why inhibit enzymes?
Certain disease states may be caused by the product of an
enzyme catalysis
Drugs can target enzymes which are present in pathogens but
not in the host
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NH2 CO2O3P
-
'round-up'
+=
O
OH
O3PO CO
2
CO2
OH
O3PO OH
CO2
O3PO CO2
O
OH
CO2
CO2
OH
O2C CO
2
O
EPSP synthase
glucose
PEP
EPSP
prephenate chorismate
phenylalaninetyrosine
tryptophan
-
-=
-
=+ = -
S-3-P
-
-
- -
The Shikimate Pathway
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[Angiotensin-I]
H2N -Asp -Arg -Val -Tyr -Ile -His -Pro -Phe -His -Leu -CO
2H
Angiotensin- II
Smooth musclecontracton
Aldosterone
secretion
Increasedperipheralresistance
Na -retention
Increasedextracellularfluid volume
Hypertension
A C E
N
CO2H
SH
O
Captopril
NN
O
O COOH
EtO
H
Enalapril
Anti hypertensive agents
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Penicillins and the bacterial cell-wall biosynthesis
D-ala-D-ala
pentaglycine
carbohydrate chain
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OH
NH2
O
N
N
S
O
CO2
-
H
Amoxycillin
N
O OH
OCO
2
-
Clavulanate(beta-lactamase inhibitor)
-Lactamase
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N
NH
O
O
N
NH
O
O
CH3
sugar sugar
Thymidylate synthase
N
N
N
NH
NH2
NH
NH
O
OH
CH
CO2
CH2CH
2CO
2--
N
N
N
NH
NH2
NH
NH
O
OH
CH
CO2
CH2CH2CO2
-
-
N
N NH
NN
NH2
HO
NH
CH CH2CH2CO2
CO2
OH
-
-
-
H
DHF reductase
N5-N10-methylene-THF
dihyrdofolate
tetrahydrofolate
NADPH, H+
H3N COO
OH
+ _
H3N COO+ _
N
NH
O
O
N
NH
O
O
CH3
sugar sugar
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N
N
N
NH
NH2
NH
NH
O
OH
CH
CO2
CH2CH
2CO
2--
-
dihydrofolate
N
N
N
NNH2
NH
NH
O
OH
C
H
CO2
CH2CH
2CO
2--
-
folic acid
N
NNH2
NH2
OMe
OMe
OMe
treimthoprim
DHFR inhibitor
NH2
NH2
NN SO
2
NH2
prontosil
N
N
N
NNH2
N NH
O
NH2 CH
3
CH
CO2
CH2CH
2CO
2--
-
methotrexate
N
O
SO2NNH2H
sulfamethoxazole
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OH
OH H2NHN
CH3
CO2H
CARBIDOPA
OH
NH2
CO2H
tyrosine
OH
OH
NH2
dopamine
OH
OH NH2
CO2H
L-DOPA
DOPA
decarboxylase
DOPAMINE
(blood)
DOPAMINE(brain)
Inhibits blood DOPA decarboxylase
Does NOT cross the blood-brain barrierReduces DOPA intake by 75%
L-DOPA
L-DOPA(brain)
(blood)
DDase
DDase
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NN
NN
OH
OH
OH
H
uric acid
O
NN
NN
OH
O3PO
OH OH
NH2
=
GMP
O
NN
N
N
NHH
O3PO
OH OH
= AMP
NN
NN
OH
H
hypoxanthine
NN
NN
OH
OHH
oxidase
xanthine
xanthine
oxidase
HGPRTase
N
N N
N
OH
H
allopurinol
N
N N
N
OH
OHH
alloxanthine
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CO2H
Arachidonic acid
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O
O
MeSO2
rofecoxib
COOH
O
NO2
NH
S
CH3
OO
N N
F3C
CH3
SO2NH
2
celecoxib
OAc
COOH
COX inhibitors
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Perna Canaliculus
www.lyprinol.com
Principal Ingredients
Natural mono-unsaturated Olive oil 100 mg
Lyprinol GLM pat. lipids (Eicosatetraenoic acid) 50 mg
Vitamin E (D-alpha-Tocepherol) as antioxidant -
0.225 mg.
natural lipoxygenase inhibitor