Transcript Receptors as Drug Targets

Chapter 8
Notes on Drug Design
M
M
M
RE
RE
R
Signal transduction
• Agonists are drugs designed to mimic the natural messenger
• Agonists should bind and leave quickly - number of binding interactions
is important
• Antagonists are drugs designed to block the natural messenger
• Antagonists tend to have stronger and/or more binding interactions,
resulting in a different induced fit such that the receptor is not activated.
Design of agonists
•Agonists mimic the natural messenger of a receptor
• Agonists bind reversibly to the binding site and produce the same induced fit as the
natural messenger - receptor is activated
• Similar intermolecular bonds formed as with natural messenger
• Agonists are often similar in structure to the natural messenger
• The agonist must have the correct binding groups
• The binding groups must be correctly positioned to interact with complementary
binding regions
• The drug must have the correct shape to fit the binding site
Agonist
Agonist
Agonist
Induced fit
RE
RE
R
Signal transduction
Design of a agonist and receptor
Binding groups
van der Waals
binding region
H-bond
binding region
O
H
H
O2C
OH
NH2Me
Neurotransmitter
Binding site
Receptor
Ionic binding region
Design of an agonist and receptor
H
O
H
H
O
O
NH2Me
O C
2
Receptor
O
NH2Me
H
H
Binding site
O C
2
H
INDUCED
FIT
Binding site
Receptor
Induced fit allows stronger binding
interactions
Design of an agonist
Ionic
binding
group
H-bonding
group
HO
van der Waals
-bonding
group
NH2Me
H
H2N
NH2Me
HO
NHMe
HO
H
H
H
Me
Hypothetical
neurotransmitter
NH2Me
H
Possible agonists with similar binding groups
Compare Binding groups:
• Identify important binding interactions in natural messenger
• Agonists are designed to have functional groups capable of the same interactions
• Usually require the same number of interactions
Design of an agonist
H
H
CH2Me
NH2Me
H
H
I
II
H
H
O
O
O
H
CH2Me
2
C
H
Binding site
Receptor
Structure I has one weak binding
group - negligible activity
H
NH2Me
O
2
C
H
Binding site
Receptor
Structure II has 2 of the 3 required
binding groups - weak activity
Design of an agonist
No interaction
OH
OH
H
H
O
N H 2M e
H
NH M e
2
O 2C
H
H
Binding site
2 Interactions only
• Binding groups must be positioned such that they can interact with
complementary binding regions at the same time
• Example has three binding groups, but only two can bind simultaneously
• Example will have poor activity
Design of an agonist
Mirror
H
H
O
H
H
O
Enantiomers of a
chiral molecule
O
NH2Me
MeH2N
H
H
H
O
O
O
NH2Me
H
Binding site
3 interactions
2
C
H
O
NH2Me
2
C
OH
Binding site
2 interactions
• One enantiomer of a chiral drug normally binds more effectively than
the other
• Different enantiomers likely to have different biological properties
Design of an agonist
H
Steric block
O
H
N
H2
CH 3
No Fit
H
O
Me
Me
Steric block
O2 C
Binding site
• Agonist must have correct size and shape to fit binding site
• Groups preventing access are called steric shields or steric blocks
Design of antagonists
• Antagonists bind to the binding site but fail to produce the correct induced fit receptor is not activated
• Normal messenger is blocked from binding
Perfect Fit
(No change in shape)
H
H
H
O
N
O
Me
H
Binding site
H
O C
2
Design of antagonists
OH
O C
2
Receptor binding site
Extra binding regions
Design of antagonists
Antagonists can form binding interactions with extra binding regions neighboring the
binding site for the natural messenger
Hydrophobic
binding region
Extra hydrophobic
binding region
HO
H-bond
binding region
HO
H
NH2Me
Hypothetical
neurotransmitter
Ionic binding
region
-
O
O
Asp
Design of antagonists
Induced fit resulting from binding of the normal messenger
Hydrophobic
region
Hydrophobic
region
HO
HO
HO
Induced fit
HO
H
NH2Me
H
NH2Me
-
O
O
O
Asp
O
Asp
Design of antagonists
Different induced fit resulting from extra binding interaction
Hydrophobic
region
Hydrophobic
region
Hydrophobic
region
HO
HO
HO
HO
HO
H
H
NHMe
-
NHMe
O
O
-
Asp
O
O
Asp
Initial binding
Different induced fit
Irreversible antagonists
X
Covalent Bond
X
OH
OH
O
Irreversible antagonism
• Antagonist binds irreversibly to the binding site
• Different induced fit means that the receptor is not activated
• Covalent bond is formed between the drug and the receptor
• Messenger is blocked from the binding site
• Increasing messenger concentration does not reverse antagonism
• Often used to label receptors
Irreversible antagonists
O
O
HO
Cl
Cl
N
Cl
Cl
Propylbenzilylcholine mustard
1
Cl
Irreversible
binding
Nu
Nu
Nu
Nu
Antagonist
binding site
Receptor
Agonist
binding site
2
Cl
Receptor
Allosteric antagonists
Binding site
unrecognisable
Binding site
ACTIVE SITE
(open)
Receptor
ENZYME
Allosteric
binding site
Induced
fit
(open)
Receptor
ENZYME
Antagonist
• Antagonist binds reversibly to an allosteric binding site
• Intermolecular bonds formed between antagonist and binding site
• Induced fit alters the shape of the receptor
• Binding site is distorted and is not recognised by the messenger
• Increasing messenger concentration does not reverse antagonism
Antagonists by the umbrella effect
• Antagonist binds reversibly to a neighbouring binding site
• Intermolecular bonds formed between antagonist and binding site
• Antagonist overlaps the messenger binding site
• Messenger is blocked from the binding site
messenger
Binding site
for antagonist
Binding site
for messenger
Receptor
Antagonist
Receptor
Partial agonists
Agents which act as agonists but produce a weaker effect
Partial
agonist
H
H
O
1
Slight shift
H
H
NHM e
O
O
O 2C
H
Receptor
NHM e
O 2C
2
Partial opening
of an ion channel
O
H
Receptor
Possible explanations
• Agent binds but does not produce the ideal induced fit for maximum effect
• Agent binds to binding site in two different modes, one where the agent acts
as an agonist and one where it acts as an antagonist
• Agent binds as an agonist to one receptor subtype but as an antagonist to
another receptor subtype
Inverse agonists
Properties shared with antagonists
• Bind to receptor binding sites with a different induced fit from the normal
messenger
• Receptor is not activated
• Normal messenger is blocked from binding to the binding site
Properties not shared with antagonists
• Block any inherent activity related to the receptor (e.g. GABA receptor)
• Inherent activity = level of activity present in the absence of a chemical
messenger
• Receptors are in an equilibrium between constitutionally active and inactive
forms
Explanation of how drugs affect receptor equilibria
A) Resting state
Agonist binding site
Inactive conformations
B) Addition of agonist
C) Addition of antagonist
D) Addition of inverse agonist
E) Addition of partial agonist
Active conformation
Desensitization
• Receptors become desensititized on long term exposure to agonists
• Prolonged binding of agonist leads to phosphorylation of receptor
• Phosphorylated receptor changes shape and is inactivated
• Dephosphorylation occurs once agonist departs
1
H
Ion channel
O2C (closed)
O
Agonist
Receptor
NH3
Desensitization
• Receptors become desensititized on long term exposure to agonists
• Prolonged binding of agonist leads to phosphorylation of receptor
• Phosphorylated receptor changes shape and is inactivated
• Dephosphorylation occurs once agonist departs
O2C
H
O
Agonist
NH3
Receptor
•Induced fit alters protein shape
•Opens ion channel
Desensitization
• Receptors become desensititized on long term exposure to agonists
• Prolonged binding of agonist leads to phosphorylation of receptor
• Phosphorylated receptor changes shape and is inactivated
• Dephosphorylation occurs once agonist departs
O2C
H
O
Agonist
Receptor
NH3
Desensitization
• Receptors become desensititized on long term exposure to agonists
• Prolonged binding of agonist leads to phosphorylation of receptor
• Phosphorylated receptor changes shape and is inactivated
• Dephosphorylation occurs once agonist departs
O2C
H
O
Agonist
NH3
P
Receptor
• Phosphorylation alters shape
• Ion channel closes
• Desensitization
Sensitization
• Receptors become sensititized on long term exposure to antagonists
• Cell synthesises more receptors to compensate for blocked receptors
• Cells become more sensitive to natural messenger
• Can result in tolerance and dependence
• Increased doses of antagonist are required to achieve same effect (tolerance)
• Cells are supersensitive to normal neurotransmitter
• Causes withdrawal symptoms when antagonist withdrawn
• Leads to dependence
Sensitization
Neurotransmitter
Normal response
Antagonist
No response
Receptor
synthesis
No response
Receptor
synthesis
Sensitization
Response
Increase
antagonist
Excess response
Dependence
No response
Stop
antagonist
Tolerance
No response
Design of an antagonist for the estrogen receptor
His 524
Me OH
H
H
Glu353
H
H
O
H2O
Hydrophic skeleton
Arg394
Oestradiol
• Phenol and alcohol of estradiol are important binding groups
• Binding site is spacious and hydrophobic
• Phenol group of estradiol is positioned in narrow slot
• Orientates rest of molecule
• Acts as agonist
H
Action of the oestrogen receptor
Binding
site
AF-2
regions
H12
Coactivator
Coactivator
Oestradiol
DNA
Oestrogen
receptor
Dimerisation &
exposure of
AF-2 regions
Nuclear
transcription
factor
Transcription
Design of an antagonist for the estrogen receptor
Asp351
N
H
Side
chain
His 524
O
Glu353
O
OH
H
O
S
Arg394
Raloxifene
Raloxifene is an antagonist (anticancer agent)
Phenol groups mimic phenol and alcohol of estradiol
Interaction with Asp-351 is important for antagonist activity
Side chain prevents receptor helix H12 folding over as lid
AF-2 binding region not revealed
Co-activator cannot bind
Tamoxifen as an antagonist
for the estrogen receptor
O
Me2N
CH2CH3
Anticancer agent