0Receptors as Drug Targets Ch 8

8/11/2019 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



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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



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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



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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



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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


Induced fit alters protein shape Opens ion channel


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Receptor

O

H

Agonist NH3

O2C



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Receptor

O

H

Agonist P

O2C

NH3


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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0Receptors as Drug Targets Ch 8

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