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

O MORPHINE
NMe

HO
Important groups for analgesic activity

HO

O MORPHINE
NMe

HO

Analgesik: obat yang digunakan sebagai penahan sakit

Analgesik bersifat narkotik: menekan sistem saraf utama dan

mengubah persepsi terhadap kesakitan
Important groups for analgesic activity

HO

O MORPHINE
NMe

HO
Analgesic pharmacophore for opioids

HO

N
 HO
HO

O
H3C NMe
NMe
CH3
HO METAZOCINE
MORPHINE
HO

NMe

LEVORPHANOL
 HO
HO

O
H3C NMe
NMe
CH3
HO METAZOCINE
MORPHINE
HO

NMe

LEVORPHANOL
 3D pharmacophore

Defines relative positions in space of important binding groups

Example

HO
x N

x HO

N
Important groups for activity

HO

O MORPHINE
NMe

HO
HO

O
NMe

HO
O

Ar

N
O 2.798 A
18.5o
Ar
150o

4.534 A
7.098 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

4.534 A
7.098 A

11.3o
N
 Bonding type
pharmacophore
2.798 A
HBA 18.5o
vdW
150o

4.534 A
7.098 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

Rotatable NH2
bonds
HO NH2 HO NH2 HO

HO HO HO
I II
Dopamine

Locked bonds
Pharmacophores from target binding sites

H-bond
basic or donor or
positive acceptor
center

H-bond
basic or donor or
positive acceptor
center
aromatic
center
aromatic
center

Pharmacophore
 Pharmacophore triangles

Pharmacophore triangles for dopamine

Basic
NH2 NH2 NH2
HBD/HBA
HO HO HO

Ar
Ar
HO HO 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
O2N
CH3
Cl

OH CH3