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INHIBITORS AS DRUGS
By : Ms.Tabhitha K
Guide : Mr. Sampath Ayyappa G, M.Pharm
ENZYMES - INTRODUCTION
ENZYME INHIBITION
• Enzyme inhibitors can be grouped into two general categories:
1. Reversible inhibitors
2. Irreversible inhibitors
• Reversible enzyme inhibitors can be classified into three
categories:
1. Competitive reversible inhibitors
2. Non-competitive reversible inhibitors and
3. Uncompetitive reversible inhibitors
Kon
E + I .
E I
Koff
+S -S
E .S E .P E + P
Asp Arg Val Tyr Ile His Pro Phe His Leu
Angiotensin I (decapeptide)
aminopeptidase N aminopeptidase A
Asp Arg Asp
aminopeptidase N ACE
Val Tyr Ile His Pro Phe Arg Val Tyr Ile His Pro Phe Arg Val Tyr Ile His Pro Phe His Leu
Arg His Leu
Angiotensin IV Angiotensin III
(hexapeptide)
Renin-angiotensin system
2+
Zn
- -
--- OH
-
R2' O R1' O R1" O R2"
-
N C C N C C N C C N C COO
H H H H H H H H
S1"
---
--
S1' 2+
Zn
-- --
-- +
--
-- --
R O CH2 - carboxypeptidase A
O
N C C N C C substrate
H H H H O
---
--- ---
--- ---
-- --
-- --
CH2
O O
C C C C (R)-2-benzylsuccinic
O H2 H O acid
---
--
S1'
--- 2+
---
Zn +
--
R O CH2 O
products of
N C C H2N C C hydrolysis
H H O H O
CH2
O O (R)-2-benzylsuccinic
C C C C
O H2 H acid
O
The collected products hypothesis of enzyme inhibition
B S2'
S1 2+ S1'
Zn --- +--
--- --- --- H ---
ACE
--- --- --- --- - --
--
- - - - -
R3' O R2' O O
N C N C N substrate
H H H H --- --- O
--- --- --- ---
--- --- ---
- - - - ---
-
O R2' O O
C C carboxyalkylproline
--- N --
O H2 H --- --- O
--- --- -- --- ---
H3C ---
- --- --
-- -- ---
H - -
HS N --- R2' O
- O
mercaptoalkylproline
S C C N
O H2 H O
CO2H
Captopril Hypothetical binding of carboxyalkylproline
and mercaptoalkylproline derivatives to ACE
S1
Hypothetical interactions of enalaprilat with ACE
B S2'
S1'
ZnII H + ACE
CH2 CH3
O O O
H
N C N N Substrate (peptide)
H H H O
CH2 CH3 O
O O
N C
H
N
Product
H2N
H H
O O
O O
CH2 CH3 O O
H
C N N Enalaprilat
H2 H O
CH2 CH2
H2C H3C esterase H2C CH3
H H
H H
N N
H2CH3COOC N HOOC
N
H H
O O
CO2H CO2H
Enalapril (prodrug) Enalaprilat
CH2 NH2
H2C (CH2)4
CO2H
H
R N
N
H
O
CO2H
Lisinopril
DESIGN OF ALTERNATIVE SUBSTRATE
INHIBITORS
NH2
dihydropteroate
dihydrofolate
tetrahydrofolate
Biosynthesis of bacterial folic acid
H
H2N N N
O O
N O P O P O
N
O O
OH
dihydropteroate diphosphate
O H2N SO2NH2
dihydropteroate synthase H2N
O sulfanilamide
PABA
H
H2N N N
H
H2N N N
N
N O N
OH N N
H
O OH N SO2NH2
dihydropteroate H
-O
Ph O
CH3O
CH2 C
C C N C C Pro
H2 H H
Enalaprilat
2+ **2
2+ Zn
Zn
R1' O R1"
R1' O R1"
-H NC NC C HN C
NC C 2 HH H
HH H O
O H
H
HB B
+
-O
Ph O
CH3O
CH2 C
C C N C C Pro
H2 H H
Enalaprilat
Hypothetical mechanism for ACE catalyzed peptide hydrolysis
DESIGN OF MULTISUBSTRATE ANALOGS
2 -OOC PO3
2 -OOC ** -OOC
PO 3
O O H
+ H2N H2N N
NH2 COO-
O NH2 COO- O COO -
O
NH2
carbamoyl L-aspartic 2 - N-carbamoyl-
phosphate acid PO 3
-OOC L-aspartate
CH2
O N COO -
H
PALA
N-phosphonoacetyl
-L-aspartate