1. Drug Discovery and Design
How are drugs discovered and designed?

2. The ancestors of drugs – potions

3. Folk remedies – Aspirin
Hippocrates
IV cent. BC
XVIII cent. AD
Felix Hoffmann
XX cent.
Willow bark
Powedered
Willow bark
Salicylic alcohol
Salicylic acid
Acetylsalicylic
acid
tea
Salicin

4. Structure of aspirin
carboxylic acid
benzene
ester

5. Preparation of aspirin
Bitter
Low fat solubility
 poor absorption
Better taste
High fat solubility
 higher absorption
This reaction is reversed in the body

6. Your Turn. Similar structures, similar properties
Approximately 40 alternatives to aspirin have been produced—with ibuprofen and paracetamol being the most familiar.
Look at the structures of aspirin, ibuprofen and paracetamol. Identify the structural similarities and differences.
Ibuprofen
Aspirin
Paracetamol

7. Look up the symptoms that each medication is advertised to treat
Look up the symptoms that each medication is advertised to treat. Do you find any similarities or differences?
Ibuprofen

8. Look up the top side effects for each medication
Look up the top side effects for each medication. Do you find any similarities or differences?
Ibuprofen
Paracetamol
Aspirin

9. Your Turn. You Decide : Supersize my aspirin
A friend who suffers from heart disease has been told by the doctor to take one aspirin tablet a day. To save money, your friend often buys the large 300-tablet bottle of aspirin. You, on the other hand, rarely take aspirin, but cannot pass up a good bargain. You also buy the large bottle.
Why is the “giant economy size” bottle of aspirin not as good a deal for you as it is for your friend?
What chemical evidence supports your opinion?

10. One way to «discover» drugs

11. Lucky accidents - Penicillin
The discovery of penicillin was a triumph of accident, a fortunate occurrence which happened while I was working on a purely academic bacteriological problem.
– Alexander Fleming –
Penicillium
notatum
Bacterial colonies
Area of inhibited
growth

13. Penicillium
Area of
inhibition
Staphylococcus

14. Alexander
Fleming
(microbiologist)
Ernst Boris
Chain
(biochemist)
Sir Howard Walter
(pathologist)

16. Penicillin – Mechanism of action
cell wall

17. Modern drug discovery – rational approach
and design

18. Mechanism of action of drugs
Drug or
hormone

19. Stage 1. Drug discovery
Choose a drug target
Identify a bioassay
= a test used to determine
biological activity
Obtain compounds for screening

20. Stage 1. Drug design = optimization
Goal: improve activity of active compound

21. Game 1

23. Game 2

26. Game 3

28. Stage 2. Pre-clinical development
(250 compounds)
Efficacy
A > B

29. Drugs and poisons
if > 4 g/day
antileukemic

30. The dose makes the poison.

31. Stage 2. Pre-clinical development
Efficacy (as for cells) +
Safety
Side effects
Short- and long-term effects
on specific organs/systems:
Lethal dose

32. Animals and Drug Testing
Consider This:
Animals and Drug Testing
Animal right groups often target the LD50 (lethal dose for 50% of the test animals) as an example of callous indifference to animal welfare. Other groups argue that such standards are necessary to insure drug safety and effectiveness. What is your position on the issue?

33. Stage 2. Pre-clinical development
Pharmacokinetic
properties
Stability and shelf-life
Formulation
Scale-up
Price

34. Stage 3. Clinical development
(5 compounds)
Efficacy and safety (as for mice) +
Side effects

35. I’m going to give
you a drug!
Fake drug
Feels better
Feels better!!

38. (long-term toxicity)

39. Consider This: Double-Blind Study
A friend of yours is dying from AIDS. He is in a hospital where a double blind study of a new anti-AIDS drug is being tested. By the nature of the test, he may or may not get the drug. What is your opinion about this research methodology? Would you be happy about your friend taking part in the study or do you think he should be given the test drug? Why?

40. Consider This: Who should pay?
Streptokinase, a medication that dramatically increase the likelihood of surviving heart attack, costs 700 $ per dose. Who should pay for this life-prolonging drug–individuals, medical insurance, pharmaceutical companies, the government?

41. Consider This: A Lottery for Life?
In early 1996, a lottery was held to select 2000 victims of advanced AIDS to receive an experimental drug called ritonavir. In other tests, similar drugs had proved effective in almost completely suppressing the AIDS virus in most subjects. Therefore, thousands of people suffering from the disease signed up for what might be a chance at prolonged life. Do you think this is a fair way of distributing a limited supply of the drug? What are your ethical arguments?