Patrick

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Patrick An Introduction to Medicinal Chemistry
3/e Chapter 10 DRUG DESIGN OPTIMIZING TARGET
INTERACTIONS Part 2 Section 10.2
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Contents Part 2 Sections 10.2 3. Pharmacophore
3.1. Structural (2D) Pharmacophore (7
slides) 3.2. 3D Pharmacophore (6
slides) 3.3. Generalised Bonding Type
Pharmacophore 3.4. The Active Conformation
3.5. Pharmacophores from Target Binding Sites
3.6. Pharmacophoric Triangles 20 slides
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DRUG DESIGN AND DEVELOPMENT
Stages
1) Identify target disease 2) Identify drug
target 3) Establish testing procedures 4) Find
a lead compound 5) Structure Activity
Relationships (SAR) 6) Identify a pharmacophore
7) Drug design- optimising target interactions
8) Drug design - optimising pharmacokinetic
properties 9) Toxicological and safety tests 10)
Chemical development and production 11) Patenting
and regulatory affairs 12) Clinical trials
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3. PHARMACOPHORE

• Defines the important groups involved in binding
• Defines the relative positions of the binding
  groups
• Need to know Active Conformation
• Important to Drug Design
• Important to Drug Discovery

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3.1 Structural (2D) Pharmacophore
Defines minimum skeleton connecting important
binding groups
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HO
MORPHINE
O
NMe
HO
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IMPORTANT GROUPS FOR ANALGESIC ACTIVITY
HO
MORPHINE
O
NMe
HO
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IMPORTANT GROUPS FOR ANALGESIC ACTIVITY
HO
MORPHINE
O
NMe
HO
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ANALGESIC PHARMACOPHORE FOR OPIATES
HO
N
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HO
NMe
H3C
CH3
METAZOCINE
MORPHINE
HO
NMe
LEVORPHANOL
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HO
HO
O
NMe
H3C
NMe
CH3
HO
METAZOCINE
MORPHINE
HO
NMe
LEVORPHANOL
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3.2 3D Pharmacophore
Defines relative positions in space of important
binding groups
Example
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IMPORTANT GROUPS FOR ACTIVITY
HO
MORPHINE
O
NMe
HO
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3.3 Generalised Bonding Type Pharmacophore
Defines relative positions in space of the
binding interactions which are required for
activity / binding
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3.4 The Active Conformation

• Need to identify the active conformation in order
  to identify the 3D pharmacophore
• Conformational analysis - identifies possible
  conformations and their activities
• Conformational analysis is difficult for simple
  flexible molecules with large numbers of
  conformations
• Compare activity of rigid analogues

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3.5 Pharmacophores from Target Binding Sites
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3.6 Pharmacophoric Triangles
Pharmacophore triangles for dopamine