Patrick

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Patrick An Introduction to Medicinal Chemistry
3/e Chapter 10 DRUG DESIGN OPTIMIZING TARGET
INTERACTIONS Part 4 Section 10.3.8
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Contents Part 4 Section 10.3.8 4.8. Simplifica
tion - Rationale - Methods (9
slides) - Example (2 slides) - Disadvantages
(14 slides) - Example of oversimplification (8
slides) 36 slides
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4.8 Simplification

• Rationale
• Lead compounds from natural sources are often
  complex and difficult to synthesise
• Simplifying the molecule makes synthesis of
  analogues easier, quicker and cheaper
• Simpler structures may fit binding site easier
  and increase activity
• Simpler structures may be more selective and less
  toxic if excess functional groups removed

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4.8 Simplification

• Methods
• Retain pharmacophore
• Remove unnecessary functional groups

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4.8 Simplification

• Methods
• Remove excess rings

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4.8 Simplification

• Methods
• Remove asymmetric centres

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4.8 Simplification

• Methods
• Simplify in stages to avoid oversimplification

• Simplification does not mean pruning groups off
  the lead
• compound
• Compounds usually made by total synthesis

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4.8 Simplification
Example

• Important binding groups retained
• Unnecessary ester removed
• Complex ring system removed

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4.8 Simplification
Example
Devazepide Excess rings removed
Asperlicin - CCK antagonist Possible lead for
treating panic attacks
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4.8 Simplification

• Disadvantages
• Oversimplification may result in decreased
  activity and selectivity
• Simpler molecules have more conformations
• More likely to interact with more than one target
  binding site.

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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Different binding site - side effects
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4.8 Simplification

• Example of oversimplification
• Simplification of opiates

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MORPHINE
C
C
O
C
C
C
C
N
SIMPLIFICATION
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LEVORPHANOL
C
C
O
C
C
C
C
N
SIMPLIFICATION
33
LEVORPHANOL
C
C
O
C
C
C
C
N
SIMPLIFICATION
34
METAZOCINE
C
C
O
C
C
C
C
N
SIMPLIFICATION
35
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
36
TYRAMINE
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
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AMPHETAMINE
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION