Transcript No Slide Title

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
HO
O
NMe
H3C
NMe
CH3
METAZOCINE
HO
MORPHINE
HO
NMe
LEVORPHANOL
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HO
HO
O
NMe
H3C
NMe
CH3
METAZOCINE
HO
MORPHINE
HO
NMe
LEVORPHANOL
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3.2 3D Pharmacophore
Defines relative positions in space of important binding groups
Example
HO
x
N

HO
x

N
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IMPORTANT GROUPS FOR ACTIVITY
HO
MORPHINE
O
NMe
HO
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HO
O
NMe
HO
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O
Ar
N
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O
2.798 A
18.5o
Ar
150o
7.098 A
4.534 A
11.3o
N
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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
HBD
HBA
Base
HBA
y
Ar
x


y
x
HBD
HBA

Ar
Base
HBA
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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
NH2
HO
HO
NH2
rotatable bonds
Dopam ine
HO
NH2
HO
HO
HO
II
I
Locked bonds
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3.5 Pharmacophores from Target Binding Sites
SER
Binding
site
ASP
O
H
CO2
H-bond
donor or
acceptor
basic or
positive
center
H-bond
donor or
acceptor
basic or
positive
center
aromatic
center
aromatic
center
Pharmacophore
PHE
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3.6 Pharmacophoric Triangles
Pharmacophore triangles for dopamine
Basic
NH2
NH2
NH2
HBD/HBA
HO
HO
HO
Ar
Ar
HO
HO
HO
HBD/HBA
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