1.

Receptor function
• Receptors contain a binding site (hollow or cleft in the receptor
surface) that is recognised by the chemical messenger

• Binding of the messenger involves intermolecular bonds

• Binding results in an induced fit of the receptor protein

• Change in receptor shape results in a ‘domino’ effect

• Domino effect is known as signal transduction, leading to a

chemical signal being received inside the cell

• Chemical messenger does not enter the cell. It departs the receptor
unchanged and is not permanently bound

80
2. The Binding Site

• A hydrophobic hollow or cleft on the receptor surface -

equivalent to the active site of an enzyme

• Accepts and binds a chemical messenger

• Contains amino acids which bind the messenger

• No reaction or catalysis takes place

Binding site
Binding site

ENZYME

81
3. Messenger Binding
3.1 Introduction

Messenger
M

Induced fit

Notes:

• Binding site is nearly the correct shape for the messenger

• Binding alters the shape of the receptor (induced fit)
• Altered receptor shape leads to further effects - signal transduction

82
3. Messenger Binding
3.2 Bonding forces
• Ionic
• H-bonding
• van der Waals

Example vdw
interaction

H-bond
Binding site
H ionic Phe
Ser O
bond
CO2

Asp

Receptor
83
3. Substrate Binding
3.2 Bonding forces
• Induced fit - Binding site alters shape to maximise intermolecular bonding

Ser O H Phe
O H Phe
Ser
CO2
CO2 Induced
Fit Asp
Asp

Intermolecular bonds not optimum Intermolecular bond lengths optimised

length for maximum binding strength

84
4. Overall Process of Receptor/Messenger Interaction

M M

RE RE
R

Signal transduction
Notes:

• Binding interactions must be strong enough to hold the messenger sufficiently long
for signal transduction to take place

• Interactions must be weak enough to allow the messenger to depart

• Implies a fine balance of binding interactions

• Messengers tend to bind and depart quickly 85

4. Overall Process of Receptor/Messenger Interaction

M M

RE RE
R

Signal transduction
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. 86
• Good communication between the messengers and
receptors leads to normal working of the human body
• If the communication becomes faulty then it leads to
ailments (such as depression, heart problems, schizophrenia, muscle fatigue,
etc).
– If too many messengers were released; the target cell start
to 'overheat'.
– Alternatively, if too few messengers were sent out, the cell
become 'sluggish'.
• Drugs can play a role by:
– Acting as replacement messengers (if there is a lack of the body's
own messengers).
– By blocking the receptors for the natural messengers (if
there are too many host messengers).
– Drugs of the first type are known as agonists and those of
the latter type are known as antagonists.

87
 Receptor Superfamilies

1. Ion channel receptors

2. Membrane bound enzyme

MEMBRANE
BOUND
3. G‐protein coupled receptors

4. Kinase linked receptors

5. Intracellular receptors

88
5. Design of Agonists
5.1 Introduction
• 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

Agonist Agonist Agonist

Induced fit

RE RE
R

Signal transduction
89
5. Design of Agonists
5.2 Requirements

• 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

90
5. Design of Agonists
5.3 Example of a hypothetical messenger and receptor

H-bond van der Waals

binding region Ionic binding region
binding region
Binding groups
H
O
O 2C

H OH
NH2Me Binding site

Neurotransmitter Receptor

91
5. Design of Agonists
5.3 Example of a hypothetical messenger and receptor

H H H H O C
O 2
O
O O
O C
NH2Me 2 NH2Me
H H

INDUCED
Binding site FIT Binding site

Receptor
Receptor

Induced fit allows stronger binding interactions

92
5. Design of Agonists
5.4 Correct binding groups

Ionic
H-bonding
binding
group
group

HO HO
NH2Me H2N HO NH2Me
NH2Me NHMe H
van der Waals H H H
-bonding
group
Me H
Hypothetical Possible agonists with similar binding groups
neurotransmitter

Notes:
• Identify important binding interactions in natural messenger
• Agonists are designed to have functional groups capable of same
interactions
• Usually require same number of interactions
93
5. Design of Agonists
5.4 Correct binding groups
H H
CH2Me NH 2Me
H H

I
II

H H
O O
O C H O C
H 2 NH 2Me 2
C H 2Me
H H

Binding site Binding site

Receptor Receptor

Structure I has one weak binding Structure II has 2 of the 3 required

group - negligible activity binding groups - weak activity

94
5. Design of Agonists
5.5 Correct position of binding groups

No interaction

OH
OH H H
O
NH M e O2 C
H 2
N H Me
2 H
H

Binding site

2 Interactions only

Notes
• 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 95
5. Design of Agonists
5.5 Correct position of binding groups
Mirror
H H
O
NH2Me MeH2N
O Enantiomers of a
H H chiral molecule

H H H
O O O
O C H O C
NH2Me 2 NH2Me 2

H OH

Binding site Binding site

3 interactions 2 interactions

Notes
• One enantiomer of a chiral drug normally binds more effectively than the other
• Different enantiomers likely to have different biological properties
96
5. Design of Agonists
5.6 Size and shape

H
Steric block
O CH 3
N
H2 No Fit
H

H
O Me
Steric block O2C

Binding site

Notes
• Agonist must have correct size and shape to fit binding site
• Groups preventing access are called steric shields or steric blocks
97
6. Allosteric modulators
Agents which enhance receptor activity by binding to an allosteric
binding site rather than the messenger binding site

Example
Benzodiazepines target the allosteric binding site of the GABAA
receptor

98
7. Reversible Antagonists

M
An

An

RE R

Notes:
• Antagonist binds reversibly to the binding site
• Intermolecular bonds involved in binding
• Different induced fit means receptor is not activated
• The antagonist does not undergo any reaction
• Level of antagonism depends on strength of antagonist binding and
concentration
• Messenger is blocked from the binding site
• Increasing the messenger concentration reverses antagonism
99
8. 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
O N O C
2
Me
H H

Binding site

100