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Chapter 8
MM
MM
EERR
• 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.
RR
MM
EERR
Signal transductionSignal transduction
Notes on Drug DesignNotes on Drug Design
Design of agonistsDesign 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
EE
AgonistAgonist
RR EE
AgonistAgonist
RR
Signal transductionSignal transduction
AgonistAgonist
RR
Induced fitInduced fit
van der Waalsbinding regionH-bond
binding regionIonic binding region
Binding groups
Neurotransmitter
OO2C
H
Binding site
Receptor
NH2Me
OHH
Design of a agonist and receptorDesign of a agonist and receptor
O
NH2Me
H
HO
O2
C
H
Binding site
Receptor
O
NH2Me
H
HO
O2
CH
Binding site
Receptor
INDUCED FIT
Induced fit allows stronger binding interactions
Design of an agonist and receptorDesign of an agonist and receptor
Hypothetical neurotransmitter
HONH2Me
H
Compare 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
H-bondinggroup
van der Waals-bondinggroup
Ionic bindinggroup
H2NNH2Me
HNHMe
HO HONH2Me
HH
HMe
Possible agonists with similar binding groups
Design of an agonistDesign of an agonist
OO
2C
H
Binding site
Receptor
OO
2C
H
Binding site
Receptor
HCH2Me
H
Structure II has 2 of the 3 required binding groups - weak activity
HNH2Me
H
I
HCH2Me
H
II
HNH2Me
H
Structure I has one weak binding group - negligible activity
Design of an agonistDesign 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
HN H
2M e
O H
H
OO 2C
H
Binding site
2 Interactions only
H
NH2Me
H
OH
No interaction
Design of an agonistDesign of an agonist
• One enantiomer of a chiral drug normally binds more effectively than the other• Different enantiomers likely to have different biological properties
OO
2C
H
Binding site
3 interactions
O
NH2Me
H
HO
O2
C
H
Binding site
2 interactions
OH
NH2Me
H
ONH2Me
H
H
OMeH2N
H
H
Mirror
Enantiomers Enantiomers of a chiral of a chiral moleculemolecule
Design of an agonistDesign of an agonist
O
NH 2
H
H
Me
CH 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
CH 3
Steric block
Me
Steric block
Design of an agonistDesign of an agonist
Design of antagonistsDesign 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
Me
H
H
OO
2C
H
Binding site
Perfect Fit(No change in shape)
Design of antagonistsDesign of antagonists
OHO
2C
Receptor binding site
Extra binding regions
O
O
Asp
-
HO
Design of antagonistsDesign of antagonistsAntagonists can form binding interactions with extra binding regions neighboring the binding site for the natural messenger
Extra hydrophobic binding region
Hydrophobic binding region
Ionic bindingregion
H-bondbinding region
Hypothetical neurotransmitter
NH2Me
HO
H
Hydrophobic region
O
O
Asp
-
HO
Design of antagonistsDesign of antagonistsInduced fit resulting from binding of the normal messenger
NH2Me
HO
H
Hydrophobic region
O
O
Asp
HO
-
NH2Me
HO
HInduced fit
Hydrophobic region
O
O
Asp
HO
Hydrophobic region
HO
Initial binding
-
Design of antagonistsDesign of antagonistsDifferent induced fit resulting from extra binding interaction
NHMe
HO
H
Hydrophobic region
O
O
Asp
HO
Different induced fit
-NHMe
HO
H
Irreversible antagonistsIrreversible 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
1
Nu
Nu
Receptor
Propylbenzilylcholine mustard
Cl
Cl
Agonist binding site
Antagonistbinding site
Cl
Cl
HOO
O
NCl
Cl
Irreversible antagonistsIrreversible antagonists
Nu
Nu
Receptor
2Irreversible binding
Allosteric antagonistsAllosteric 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)
ENZYMEReceptor
AllostericAllostericbinding sitebinding site
Binding siteBinding site
(open)ENZYMEReceptor
Inducedfit
Binding siteBinding siteunrecognisableunrecognisable
Antagonist
Antagonists by the umbrella effectAntagonists 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
Antagonist
Binding sitefor antagonist
Binding sitefor messenger
messenger
Receptor Receptor
Partial agonistsPartial agonists
Agents which act as agonists but produce a weaker effect
Partialagonist Slight shift
Partial openingof an ion channel
Receptor
OO 2C
H
1
NHMeO
H
H H
Receptor
O
O 2C
2
NHMeO
H
H
Possible explanationsPossible 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 agonistsInverse agonists
Properties shared with antagonistsProperties 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 antagonistsProperties 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 equilibriaExplanation of how drugs affect receptor equilibria
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
DesensitizationDesensitization
• 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)
AgonistNH3
Receptor
O
H
AgonistNH3
O2C
DesensitizationDesensitization
• 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 shapeInduced fit alters protein shape•Opens ion channelOpens ion channel
Receptor
O
H
AgonistNH3
O2C
DesensitizationDesensitization
• 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
H
AgonistP
O2C
NH3
DesensitizationDesensitization
• 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
SensitizationSensitization• 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
SensitizationSensitization
Antagonist
Neurotransmitter
Normal response
Receptorsynthesis
No response
Response
StopantagonistExcess response No response
Increaseantagonist
Tolerance
Receptorsynthesis
Sensitization
Dependence
No response
No response
O
Me OH
H
H H
H
H
H2O
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 receptorDesign of an antagonist for the estrogen receptor
Action of the oestrogen receptorAction of the oestrogen receptor
Oestradiol
H12
Oestrogenreceptor
Binding site
AF-2 regions
Dimerisation &exposure of AF-2 regions
CoactivatorCoactivator
Nucleartranscription
factor
CoactivatorCoactivator
DNA
Transcription
OH
S
O
O
Raloxifene
Asp351
His 524
O
Glu353
Arg394
N
H
H
Side chain
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 lidAF-2 binding region not revealedCo-activator cannot bind
Design of an antagonist for the estrogen receptorDesign of an antagonist for the estrogen receptor
Anticancer agent
CH2CH3
O
Me2N
Tamoxifen as an antagonist Tamoxifen as an antagonist for the estrogen receptorfor the estrogen receptor
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