1. Pharmacophores
Chapter 13 Part 2

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

3. Structural (2D) pharmacophore
Defines minimum skeleton connecting important binding groups

4. HO O
MORPHINE
NMe
MOR025.WAV HO

5. HO O MORPHINE NMe HO Important groups for analgesic activity
MOR025.WAV HO

6. HO O MORPHINE NMe HO Important groups for analgesic activity
MOR025.WAV HO

7. Analgesic pharmacophore for opioids
MOR025.WAV

8. HO HO O H3C NMe NMe CH3 METAZOCINE MORPHINE HO NMe LEVORPHANOL
MOR025.WAV
NMe
LEVORPHANOL

9. HO HO O H3C NMe NMe CH3 HO METAZOCINE MORPHINE HO NMe LEVORPHANOL
MOR025.WAV
NMe
LEVORPHANOL

10. 3D pharmacophore
Defines relative positions in space of important binding groups
Example

11. Important groups for activityHO O
MORPHINE
NMe
MOR025.WAV HO

12. HO O
NMe
MOR028.WAV HO

13. MOR028.WAV

14. O N Ar
MOR028.WAV

15. O
7.098 A
2.798 A
4.534 A
11.3o
150o
18.5o Ar
MOR028.WAV N

16. 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

17. 3D Pharmacophore O 2.798 A Ar 4.534 A 7.098 A MOR028.WAV N 18.5o 150o

18. Bonding type pharmacophore 2.798 A HBA vdW 4.534 A 7.098 A MOR028.WAV
Ionic

19. 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
bonds I II
Dopamine
Locked bonds

20. Pharmacophores from target binding sites2 A S P
SER
PHE
Binding
site
H-bond
donor or
acceptor
aromatic
center
basic or
positive
H-bond
donor or
acceptor
basic or
positive
center
Pharmacophore
aromatic
center

21. Pharmacophore triangles
Pharmacophore triangles for dopamine

22. Identifying the pharmacophore
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.