1. DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 10
DRUG DESIGN:
OPTIMIZING TARGET INTERACTIONS
Part 4: Section

2. Contents
Part 4: Section
4.8. Simplification
- Rationale
- Methods (9 slides)
- Example (2 slides)
- Disadvantages (14 slides)
- Example of oversimplification (8 slides)
[36 slides]

3. 4.8 Simplification Rationale :
Lead compounds from natural sources are often complex and difficult to synthesise
Simplifying the molecule makes synthesis of analogues easier, quicker and cheaper
Simpler structures may fit binding site easier and increase activity
Simpler structures may be more selective and less toxic if excess functional groups removed

4. 4.8 Simplification Methods: Retain pharmacophore
Remove unnecessary functional groups

5. 4.8 Simplification Methods: Example Remove excess rings
Excess functional groups
Excess ring

6. 4.8 Simplification
Methods:
Remove asymmetric centres

7. 4.8 Simplification Methods:
Simplify in stages to avoid oversimplification
Pharmacophore
Simplification does not mean ‘pruning groups’ off the lead
compound
Compounds usually made by total synthesis

8. INT104

9. INT104

10. INT104

11. INT104

12. INT104

13. 4.8 Simplification Example Important binding groups retained
Pharmacophore
Important binding groups retained
Unnecessary ester removed
Complex ring system removed

14. 4.8 Simplification Example Devazepide Asperlicin - CCK antagonist
Excess rings removed
Asperlicin - CCK antagonist
Possible lead for treating panic attacks

15. 4.8 Simplification Disadvantages:
Oversimplification may result in decreased activity and selectivity
Simpler molecules have more conformations
More likely to interact with more than one target binding site.

16. INT115
Target binding site

17. INT116
Target binding site

18. Rotatable bonds
INT116
Target binding site

19. Rotatable bonds
INT116
Target binding site

20. Rotatable bonds
INT116
Target binding site

21. Rotatable bonds
INT116
Target binding site

22. Rotatable bonds
INT116
Target binding site

23. Rotatable bonds
INT116
Target binding site

24. Rotatable bonds
INT116
Target binding site

25. Rotatable bonds
INT116
Target binding site

26. Rotatable bonds
INT116
Target binding site

27. Rotatable bonds
INT116
Target binding site

28. Rotatable bonds
INT117
Target binding site

29. Rotatable bonds
INT118
Different binding site - side effects

30. Example of oversimplification
Simplification of opiates

31. MORPHINE C C O C C C C
MOR062.WAV N
SIMPLIFICATION

32. LEVORPHANOL C C O C C C C
MOR064.WAV N
SIMPLIFICATION

33. LEVORPHANOL C C O C C C C
MOR064.WAV N
SIMPLIFICATION

34. METAZOCINE C C O C C C C
MOR065.WAV N
SIMPLIFICATION

35. C C O C C C C
MOR065.WAV N
OVERSIMPLIFICATION

36. TYRAMINE C C O C C C C
MOR065.WAV N
OVERSIMPLIFICATION

37. AMPHETAMINE C C O C C C C
MOR065.WAV N
OVERSIMPLIFICATION