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Cell Membrane
Exterior
High [Na+]
Proteins
Phospholipid
Bilayer
Interior
High [K+]
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Cell Membrane
CH2CH2NMe3
Polar
Head
Group
Polar
Head
Group
O
O
P
O
O
CH2 CH
O
O
CH2
O
O
Hydrophobic Tails
Hydrophobic Tails
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Drug targets
Lipids
Cell membrane lipids
Proteins
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
Nucleic acids
DNA
RNA
Carbohydrates
Cell surface carbohydrates
Antigens and recognition molecules
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Drug targets
Binding
regions
Drug
Binding
groups
Intermolecular
bonds
Binding site
Binding
site
Drug
Drug
Macromolecular target
Unbound drug
Macromolecular target
Bound drug
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Intermolecular bonding forces
O
Drug
O
O
Drug NH3
Target
H3N Target
O
- +
X H
Drug
Y Target
HBD
HBA
Drug Y
HBA
+ H X
Target
HBD
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Desolvation penalties
H
O
H
H
O
H
H
O
O
H
C
R
O
R
H
O
H
O
C
R
R
H
H
C
H
Binding site
O
O
R
Binding site
Desolvation - Energy penalty
R
Binding site
Binding - Energy gain
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O
7. Drug Targets - Cell Membrane Lipids
TUNNEL
HO2C
OH
OH CO2H
Sugar
Sugar
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
Polar tunnel formed
Escape route for ions
CELL
MEMBRANE
Sugar
HO2C
Sugar
OH
OH
CO2H
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Drug Targets - Carbohydrates
Carbohydrate 'tag'
Cell
membrane
Ceramide 'anchor'
Carbohydrate 'tag'
HO
O
SUGARS O
O
HO
(CH2)16CH3
HN
O
OH
Carbohydrates
(CH2)12CH3
OH
Ceramide unit
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2. The active site
•
Hydrophobic hollow or cleft on the enzyme surface
•
Accepts reactants (substrates and cofactors)
•
Contains amino acids which
- bind reactants (substrates and cofactors)
- catalyse the reaction
Active site
Active site
ENZYME
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Substrate binding
Induced fit
Substrate
S
Induced fit
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Substrate binding
Phe
S
O
Ser
S
O
H
CO2
Asp
Intermolecular bonds not
optimum length for
maximum bonding
Phe
Induced
fit
Ser
H
CO2
Asp
Intermolecular bond lengths optimised
Susceptible bonds in substrate strained
Susceptible bonds in substrate more
easily broken
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4. Catalysis mechanisms
Serine acting as a nucleophile
Substrate
X
H2O
HO
OH
Ser
OH
O
Ser
Ser
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Product
Overall process of enzyme catalysis
S
P
S
EE
E+S
E
ES
P
E
EP
E
E+P
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Competitive (reversible) inhibitors
S
I
I
EE
E
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Non competitive (irreversible) inhibitors
X
Covalent Bond
X
OH
OH
O
Irreversible inhibition
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Non competitive (reversible) allosteric inhibitors
Active site
unrecognisable
Active site
ACTIVE SITE
(open)
Enzyme
ENZYME
Allosteric
site
Induced
fit
(open)
Enzyme
ENZYME
Allosteric
inhibitor
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Non competitive (reversible) allosteric inhibitors
Biosynthetic pathway
S
P
P’
P’’’
P’’
(open)
Enzyme
ENZYME
Inhibition
Feedback control
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Structure and function of receptors
Nerve 1
Blood
supply
Nerve 2
Hormone
Neurotransmitters
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Structure and function of receptors
Mechanism
Induced fit
Messenger
Messenger
Messenger
Cell
Membrane
Receptor
Receptor
Cell
Cell
Receptor
Cell
message
Message
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Signal transduction
Control of ion channels
Hydrophilic
tunnel
Cell
membrane
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5. Signal transduction
5.1 Control of ion channels:
MESSENGER
ION
CHANNEL
(closed)
Cell
membrane
Cell
Ion
channel
RECEPTOR
BINDING
SITE
Lock
Gate
Ion
channel
ION
CHANNEL
(open)
Induced fit
and opening
of ion channel
Cell
membrane
Cell
membrane
Ion
channel
MESSENGER
Ion
channel
Cell
membrane
Cell
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Signal transduction
messenger
induced
fit
closed
open
G-protein
split
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Signal transduction
Enzyme
Enzyme
active site
(closed)
active site
(open)
Intracellular
reaction
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Signal transduction
messenger
messenger
induced
fit
closed
active site
open
intracellular reaction
closed
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Competitive (reversible) antagonists
M
An
An
RE
•
•
•
R
Different induced fit means receptor is not activated
No reaction takes place on antagonist
Level of antagonism depends on strength of antagonist
binding and concentration
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Non competitive (irreversible) antagonists
X
Covalent Bond
X
OH
OH
O
Irreversible antagonism
Different induced fit means that the receptor is not activated
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Non competitive (reversible) allosteric antagonists
Binding site
unrecognisable
Binding site
ACTIVE SITE
(open)
Receptor
ENZYME
Allosteric
site
Induced
fit
(open)
Receptor
ENZYME
Antagonist
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Antagonists by umbrella effect
Binding site
for antagonist
Binding site
for messenger
Receptor
messenger
Antagonist
Receptor
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Agonists
Agonist
Agonist
Agonist
Induced fit
RE
R
RE
Signal transduction
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