medchem-1

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Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 6
PROTEINS AS DRUG
TARGETS:
RECEPTOR STRUCTURE &
SIGNAL TRANSDUCTION
Part 4: Section 6.8

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Contents
Part 4: Section 6.8
5. Intracellular receptors
5.1. Structure
5.2. Mechanism
5.3. Oestrogen receptor (5 slides)
[8 slides]

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5. Intracellular receptors
• Chemical messengers must cross cell membrane
• Chemical messengers must be hydrophobic
• Example - steroids and steroid receptors

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5.1 Structure
Zinc
Zinc fingers contain Cys residues (SH)
Allow S-Zn interactions
CO2H
H2N
DNA binding region
(‘zinc fingers’)
Steroid
binding region
5. Intracellular receptors

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Cell
membrane
5.2 Mechanism
1. Messenger crosses membrane
2. Binds to receptor
3. Receptor dimerisation
4. Binds co-activator protein
5. Complex binds to DNA
6. Transcription switched on or off
7. Protein synthesis activated or inhibited
Messenger
Receptor
Receptor-ligand
complex
Dimerisation
Co-activator
protein
DNA
5. Intracellular receptors

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5.3 Oestrogen receptor
Oestradiol
H12
Oestrogen
receptor
Binding
site AF-2
regions
Dimerisation &
exposure of
AF-2 regions
Coactivator
Nuclear
transcription
factor
Coactivator
DNA
Transcription
5. Intracellular receptors

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5.3 Oestrogen receptor
O
Me OH
H
H H
H
H
H2O
His 524
Glu353
Arg394
Hydrophic skeleton
Oestradiol
• Phenol and alcohol of oestradiol are important binding groups
• Binding site is spacious and hydrophobic
• Phenol group of oestradiol positioned in narrow slot
• Orientates rest of molecule
• Acts as agonist
5. Intracellular receptors

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5.3 Oestrogen receptor
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 oestradiol
• Interaction with Asp351 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
5. Intracellular receptors

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Tamoxifen (Nolvadex)
- anticancer agent which targets oestrogen receptor
CH2CH3
O
Me2N
5.3 Oestrogen receptor
5. Intracellular receptors