medc 603 fall 20071 principles of drug design enzyme inhibition basics example: 1) statins (i)...
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MEDC 603 Fall 2007 1
Principles of Drug Design
Enzyme Inhibition Basics
E + S E:S E + P
E + I E:IKI
KM kCAT
Example: 1) Statins (I) inhibit HMG CoA Reductase (E); S = HMG CoA; P = Mevalonate2) I = Warfarin, E = reductase, S = vitamin K epoxide, P = vitamin K
Other examples: salicyclic acid, physostigmine, sulfanilamide, captopril, enalapril, finasteride, ……
]:[
]][[
IE
IEK I
E + I E:IKI
Units of KI and IC50 = M
MEDC 603 Fall 2007 2
S E+ S E E+P
Competitive Inhibition
Principles of Drug Design
E
I
I
E + S E:S P + E
E:I
IKM
kCAT
KI
][)][
1(
][][
SK
IK
SEkVi
I
OM
OCAT
MEDC 603 Fall 2007 3
OH
SCoA
COOH
OCH3
CH2CH2O
O
CH3
R'
R''
O
OOH
Substrate Inhibitor
Design of Statins
Competitive Inhibition …. Example
Principles of Drug Design
MEDC 603 Fall 2007 4
Competitive Inhibition …. Example
Principles of Drug Design
NH
N
O
O
CH3
O
HH
OH
N3
NH
N
O
O
CH3
O
HH
OH
OH
5'
3'
5'
3'
AZT Thymidine
AZT potent inhibitor of HIV-RT, the retroviral polymerase which catalyzes the
formation of proviral DNA from viral RNA.
MEDC 603 Fall 2007 5
E + S E:S E:S:I P
I
Non-Competitive Inhibition
Principles of Drug Design
S E+ S E E+P
E
I
S
I
E+P
)'
][1]([
][][
I
OM
OCAT
K
ISK
SEkVi
][
]][['
ESI
IESK I
MEDC 603 Fall 2007 6
Non-Competitive Inhibition … Example
Principles of Drug Design
Bivalirudin
Thrombin
Argatroban
Thrombin
Exosite II
Exosite I
ThrombinActive Site
Argatroban
H2N-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly
HOOC-Leu-Tyr-Glu-Glu-Pro-Ile-Glu-Glu-Phe-Asp
Bivalirudin
Competitive Non-competitive
NH
O
N
CH3
H
S
O
O
CH3 NH
NHNH2
COOH
MEDC 603 Fall 2007 7
N
NH
NN
OMe
Nevirapine
Nevirapine potent inhibitor of HIV-RT … KI ~ nM … no resemblance to any of the
natural nucleotide substrates … binds in a hydrophobic binding pocket adjacent to the substrate-binding pocket and modifies the rate of polymerization.
Non-Competitive Inhibition … Example
Principles of Drug Design
MEDC 603 Fall 2007 8
Differentiation of type of inhibition
Principles of Drug Design
Res
po
nse
[S]O
100 %
0 %
[I]= x 2x 3x 4x
Competitive Inhibition Res
po
nse
[S]O
100 %
0 %
[I]0x
2x 3x 4x
Non-competitive Inhibition
E + S E:S Response
E:I E:S:I
MEDC 603 Fall 2007 9
Irreversible Inhibition
Principles of Drug Design
E + S E:S E-S No further rxn.
Substrate behaves as an inhibitor! aka …. Suicide substrate inhibitors or Mouse trap inhibitors or Trojan horse inhibitors
N
O OH
OCOOH
NH
O OH
OCOOH
H
Nu-Enz-Ser-O
NH
OH OH
OCOOH
Ser-O
O
OSer
Enz Nu
NH
OH OH
COOH
Nu-Enz-Ser-OH
Enz- Nu
.. ..
....
..
Clavulinic acid-lactamase
N
O OH
OCOOH
NH
O OH
OCOOH
H
Nu-Enz-Ser-O
NH
OH OH
OCOOH
Ser-O
O
OSer
Enz Nu
NH
OH OH
COOH
Nu-Enz-Ser-OH
Enz- Nu
.. ..
....
..
Clavulinic acid-lactamase