0receptors as drug targets ch 8
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Chapter 8
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M
M
E
R
Agonists are drugs designed to mimic the natural messenger Agonists should bind and leave quickly - number of binding interactionsis 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 .
R
M
E
R
Signal transduction
Notes on Drug Design
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van der Waals binding region H-bond
binding region Ionic binding region
Binding groups
Neurotransmitter
O O 2 C H
Binding site
Receptor
N H 2 Me
O HH
Design of a agonist and receptor
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O N H 2 M e
H
H O O 2 C
H
Binding site
Receptor
O N H 2 M e
H
H O O
2 C H
Binding site
Receptor
INDUCEDFIT
Induced fit allows stronger bindinginteractions
Design of an agonist and receptor
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Hypotheticalneurotransmitter
HON H 2 M e
H
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
H-bondinggroup
van der Waals-bondinggroup
Ionicbindinggroup
H2NN H 2 M e
H N H M e
HO HO N H 2 M e H
H
HMe
Possible agonists with similar binding groups
Design of an agonist
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O O
2 C
H
Binding site
Receptor
O O
2 C
H
Binding site
Receptor
H C H 2 M e
H
Structure II has 2 of the 3 requiredbinding groups - weak activity
H N H 2 M e
H
I
HCH2Me
H
II
H N H 2 M e
H
Structure I has one weak bindinggroup - negligible activity
Design of an agonist
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Binding groups must be positioned such that they can interact withcomplementary binding regions at the same time Example has three binding groups, but only two can bind simultaneously Example will have poor activity
H N H
2 M e
O H
H
O O 2 C
H
Binding site
2 Interactions only
H
N H 2 M e
H
O H
No interaction
Design of an agonist
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One enantiomer of a chiral drug normally binds more effectively thanthe other
Different enantiomers likely to have different biological properties
O O
2 C
H
Binding site
3 interactions
O
N H 2 M e
H
H O
O 2
C
H
Binding site
2 interactions
O H
N H 2 M e
H
O N H 2 M e
H
H
O M e H 2 N
H
H
Mirror
Enantiomers of achiral molecule
Design of an agonist
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O N H 2
H
H
Me
C H 3
Agonist must have correct size and shape to fit binding site Groups preventing access are called steric shields or steric blocks
No Fit
O
O 2 C
H
Binding site
C H 3
Steric block
Me
Steric block
Design of an agonist
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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
O N
H
H
M e
H
H
O O 2 C
H
Binding site
Perfect Fit(No change in shape)
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Design of antagonists
OH O
2 C
Receptor binding site
Extra binding regions
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O
O
Asp
-
HO
Design of antagonists Antagonists can form binding interactions with extra binding regions neighboring the binding site for the natural messenger
Extra hydrophobicbinding region
Hydrophobicbinding region
Ionic bindingregion
H-bondbinding region
Hypotheticalneurotransmitter
N H 2 Me
H O
H
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Hydrophobicregion
O
O
Asp
HO
Hydrophobicregion
HO
Initial binding
-
Design of antagonists Different induced fit resulting from extra binding interaction
N HMe
H O
H
Hydrophobicregion
O
O
Asp
HO
Different induced fit
-N HMe
H O
H
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Irreversible antagonists
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
X
OH OH
X
O
Covalent Bond
Irreversible antagonism
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1
N u
N u
Receptor
Propylbenzilylcholine mustard
Cl
Cl
Agonistbinding site
Antagonistbinding site
C l
C l
H OO
O
NCl
Cl
Irreversible antagonists
N u
N u
Receptor
2 Irreversiblebinding
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Allosteric antagonists
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
ACTIVE SITE (open)
ENZYME Receptor
Allostericbinding site
Binding site
(open) ENZYME Receptor
Inducedfit
Binding siteunrecognisable
Antagonist
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Partial agonists Agents which act as agonists but produce a weaker effect
Partialagonist Slight shift
Partial openingof an ion channel
Receptor
O O 2 C
H
1
N H M e O
H
H H
Receptor
O O 2 C
2
N H M e O
H
H
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 actsas an agonist and one where it acts as an antagonist Agent binds as an agonist to one receptor subtype but as an antagonist toanother receptor subtype
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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 chemicalmessenger Receptors are in an equilibrium between constitutionally active and inactive
forms
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Explanation of how drugs affect receptor equilibria A) Resting state
B) Addition of agonist
C) Addition of antagonist
D) Addition of inverse agonist
E) Addition of partial agonist
Inactive conformations Active conformation
Agonist binding site
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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
Receptor
O O2C
1
H Ion channel(closed)
Agonist NH3
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Receptor
O
H
Agonist NH3
O2C
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
Induced fit alters protein shape Opens ion channel
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Receptor
O
H
Agonist NH3
O2C
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
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Receptor
O
H
Agonist P
O2C
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
Phosphorylation alters shape Ion channel closes Desensitization
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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
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Sensitization
Antagonist
Neurotransmitter
Normal response
Receptorsynthesis
No response
Response
StopantagonistExcess response No response
Increaseantagonist
Tolerance
Receptorsynthesis
Sensitization
Dependence
No response
No response
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O
Me OH
H
H H
H
H
H 2 O
His 524
Glu353
Arg394
Hydrophic skeleton
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
Design of an antagonist for the estrogen receptor
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Action of the oestrogen receptor
Oestradiol
H12
Oestrogenreceptor
Bindingsite
AF-2regions
Dimerisation &exposure of
AF-2 regions
Coactivator
Nucleartranscription
factor
Coactivator
DNA
Transcription
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OH
S
O
O
Raloxifene
Asp351
His 524
O
Glu353
Arg394
N
H
H
Sidechain
Raloxifene is an antagonist (anticancer agent)Phenol groups mimic phenol and alcohol of estradiolInteraction with Asp-351 is important for antagonist activitySide chain prevents receptor helix H12 folding over as lid
AF-2 binding region not revealedCo-activator cannot bind
Design of an antagonist for the estrogen receptor
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