Transcript Pharmacophores

Chapter 13 Part 2
Pharmacophore
• Defines the important groups involved in binding
• Defines the relative positions of the binding groups
• Need to know the active conformation
• Important to drug design
• Important to drug discovery
Structural (2D) pharmacophore
Defines minimum skeleton connecting important binding groups
HO
MORPHINE
O
NMe
HO
Important groups for analgesic activity
HO
MORPHINE
O
NMe
HO
Important groups for analgesic activity
HO
MORPHINE
O
NMe
HO
Analgesic pharmacophore for opioids
HO
N
HO
HO
O
NMe
H3C
NMe
CH3
METAZOCINE
HO
MORPHINE
HO
NMe
LEVORPHANOL
HO
HO
O
NMe
H3C
NMe
CH3
METAZOCINE
HO
MORPHINE
HO
NMe
LEVORPHANOL
3D pharmacophore
Defines relative positions in space of important binding groups
Example
HO
x
N

HO
x

N
Important groups for activity
HO
MORPHINE
O
NMe
HO
HO
O
NMe
HO
O
Ar
N
O
2.798 A
18.5o
Ar
150o
7.098 A
4.534 A
11.3o
N
Generalized bonding type pharmacophore
Note:
Defines relative positions in space of the important binding interactions which are
required for activity
Hydrogen bonding acceptor
Hydrogen bonding donor
van der Waals interaction
Ionic interaction
3D Pharmacophore
O
2.798 A
18.5o
Ar
150o
7.098 A
4.534 A
11.3o
N
Bonding type
pharmacophore
HBA
2.798 A
18.5o
vdW
150o
7.098 A
4.534 A
11.3o
Ionic
The active conformation
• The conformation adopted by a drug when it binds to its target
• Identification of the active conformation is required in order to identify the 3D
pharmacophore
• Conformational analysis identifies possible conformations and their stabilities
• Conformational analysis is difficult for flexible molecules with large numbers of
conformations
• Easier to compare activities of rigid analogues
NH2
Rotatable
bonds
HO
NH2
HO
NH2
HO
HO
Dopamine
HO
HO
I
II
Locked bonds
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
Pharmacophore triangles
Pharmacophore triangles for dopamine
Basic
NH2
NH2
NH2
HBD/HBA
HO
HO
HO
Ar
HO
HO
Ar
HO
HBD/HBA

Oxamniquine is an important Third World drug
used in the treatment of schistosomiasis
(bilharzia). Consider the structures below of
oxamniquine (A) and two of the additional drugs
tested in the design of oxamniquine. Based on
these structures, draw the pharmacophore of
oxamniquine.
H
H
N
N
NEt2
O
HN
HN
N
H3C
S
O2 N
CH3
OH
A
Cl
CH3