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Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 10
DRUG DESIGN:
OPTIMIZING TARGET
INTERACTIONS
Part 6: Section 10.3.11
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Contents
Part 6: Section 10.3.11
4.10.
4.11.
Structure based drug design
Strategy & Procedure (16 slides)
Design of Antihypertensives - ACE inhibitors
Carboxypeptidase
Carboxypeptidase mechanism
Inhibition of carboxypeptidase
Lead compounds for ACE inhibitor
Proposed binding mode
Extension and bio-isostere strategies
Extension strategies
De Novo Drug Design
[26 slides]
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4.10 Structure based drug design
Strategy
Carry out drug design based on the interactions between the lead
compound and the target binding site
Procedure
• Crystallise target protein with bound ligand
(e.g. enzyme + inhibitor or ligand)
• Acquire structure by X-ray crystallography
• Identify binding site (region where ligand is bound)
• Identify binding interactions between ligand and target
(modelling)
• Identify vacant regions for extra binding interactions
(modelling)
• ‘Fit’ analogues into binding site to test binding capability
(modelling)
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4.10 Structure based drug design
Design of Antihypertensives - ACE inhibitors
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Angiotensin I
•
•
•
•
•
ACE
Asp-Arg-Val -Tyr-Ile-His-Pro-Phe
+
His-Leu
Angiotensi n II
ACE = Angiotensin converting enzyme
Angiotensin II
- hormone which stimulates constriction of blood vessels
- causes rise in blood pressure
ACE inhibitors - useful antihypertensive agents
ACE - membrane bound zinc metalloproteinase not easily
crystallised
Study analogous enzyme which can be crystallised
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4.10 Structure based drug design
Carboxypeptidase
Peptide
3
2
1
-aa -aa -aa
Carboxypeptidase
CO2H
Peptide
-aa3-aa2
CO2H
+
Inhibition
OH
OH
O
O
L-Benzylsuccinic acid
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4.10 Structure based drug design
Carboxypeptidase mechanism
S1' pocket
S1' pocket
Zn2+
Zn2+
O
O
O
R
Natural Substrate
O
H 2N
N
H
R
O
O
O
Hydrolysis
NH2
H 2N
NH2
H 2N
145
145
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4.10 Structure based drug design
Inhibition of carboxypeptidase
S1' pocket
Zn2+
O
O
No hydrolysis
O
L-benzylsuccinic acid
O
NH2
H 2N
145
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4.10 Structure based drug design
Lead compounds for ACE inhibitor
OH
Glu-Trp-Pro-Arg-Pro-Gl n-Il e-Pro-Pro
OH
O
O
Teprotide
L-Benzylsuccinic acid
O
N
HO
O
CO2H
Succinyl proline
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4.10 Structure based drug design
Proposed binding mode
S1 pocket
S1' pocket
O
Succinyl proline
N
O
O
CO2
H 2N
H 2N
Zn 2+
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4.10 Structure based drug design
Extension and bio-isostere strategies
OH
OH
CH3
CH3
N
N
O
HS
N
O
O
CO2H
CO2H
O
CO2H
O
Captopril
S1 pocket
S1' pocket
CH3
N
HS
O
CO2
H 2N
H 2N
Zn 2+
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4.10 Structure based drug design
Extension strategies
CH3
O
N
NH
O
O
O
CO2H
N
N
H
O
O
CH3
O
CO2H
O
N
H
N
O
Enalaprilate
S1 pocket
S1' pocket
CH3
Inhibitor
O
N
N
H
O
O
CO2
H 2N
H 2N
Zn 2+
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CO2H
4.11 De Novo Drug Design
The design of novel agents based on a knowledge of the target
binding site
Procedure
• Crystallise target protein with bound ligand
• (e.g. enzyme + inhibitor or ligand)
• Acquire structure by X-ray crystallography
• Identify binding site (region where ligand is bound)
• Remove ligand
• Identify potential binding regions in the binding site
• Design a lead compound to interact with the binding site
• Synthesise the lead compound and test it for activity
• Crystallise the lead compound with target protein and identify
the actual binding interactions
• Structure based drug design
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