Receptors as Drug Targets

1
Receptors as Drug Targets

• Chapter 8

2
Notes on Drug Design

• 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.

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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

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Design of a agonist and receptor
5
Design of an agonist and receptor
Induced fit allows stronger binding interactions
6
Design of an agonist

• 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

7
Design of an agonist

• Structure II has 2 of the 3 required binding
  groups - weak activity

• Structure I has one weak binding group -
  negligible activity

8
Design of an agonist

• 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

9
Design of an agonist

• Enantiomers of a chiral molecule

3 interactions
2 interactions

• One enantiomer of a chiral drug normally binds
  more effectively than the other
• Different enantiomers likely to have different
  biological properties

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Design of an agonist

• Agonist must have correct size and shape to fit
  binding site
• Groups preventing access are called steric
  shields or steric blocks

11
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)
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Design of antagonists
13
Design of antagonists
Antagonists can form binding interactions with
extra binding regions neighboring the binding
site for the natural messenger
H-bond binding region
Ionic binding region
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Design of antagonists
Induced fit resulting from binding of the normal
messenger
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Design of antagonists
Different induced fit resulting from extra
binding interaction
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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

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Irreversible antagonists
Propylbenzilylcholine mustard
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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

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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

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Partial agonists
Agents which act as agonists but produce a weaker
effect
Partial agonist

• 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

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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 chemical messenger
• Receptors are in an equilibrium between
  constitutionally active and inactive forms

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Explanation of how drugs affect receptor
equilibria
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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

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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

H
O
Agonist
Receptor

• Induced fit alters protein shape
• Opens ion channel

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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

H
O
Agonist
Receptor
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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

H
O
Agonist
P
Receptor

• 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
Neurotransmitter
No response
Dependence
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Design of an antagonist for the estrogen receptor

• 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

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Action of the oestrogen receptor
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Design of an antagonist for the estrogen receptor
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
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Tamoxifen as an antagonist for the estrogen
receptor
Anticancer agent