Med Chem 2

Question 1

Deciding upon a suitable test…

Answer 1

Bioassay - used to test drug candidates
- choosing the right bioassay (4 consideration)

1) Simple
2) Quick
3) Relevant
4) in vitro or in vivo

Question 2

The advantages of in vitro testing…

Answer 2

1) Inexpensive
2) Easier to perform
3) Less controversial
4) Automated (often)

Question 3

Other advantages to in vitro testing…

Answer 3

1) No barrier concerns. So no worries as to whether the drug
can cross the necessary biological barriers (seen in vivo)
2) No metabolic enzymes to contend with.
3) Cell environment can be easily controlled
4) Intra and intercellular events can be monitored easily
5) Can measure potency and efficacy

Question 4

Potency

Answer 4

Potency - amount of drug required to achieve a defined biological effect

Question 5

Efficacy

Answer 5

Efficacy - measure of how effectively an agonist activates a

receptor. Drug can have a high affinity for a receptor but a low efficacy

Question 6

Advantages of in vivo testing…

Answer 6

1) important for monitoring pharmacological activity
(pharmacodynamics - effect of drug molecule on the the body)
2) important for monitoring pharmacokinetics (effect of body on the drug, e.g. absorption, distribution, metabolism and elimination)
3) allows identification of activity at undesired targets

Balance: benefit to risk ratio must always be considered.
Good activity at the desired target & minimum activity at others is the desirable scenario

Question 7

Disadvantages of in vivo tests - on animal or humans

Answer 7

1) Slow progress
2) Animal suffering
3) Pharmacokinetics - results may be misleading (intraspecies
variation)
4) Different results in different animal species
eg. 1 Penicillin methyl ester (prodrug) is hydrolysed in mice and rats but not in rabbits, dogs or humans
eg. 2 Thalidomide - teratogenic in rabbits and humans (not in mice)

Question 8

In vitro vs in vivo

Answer 8

‘in vitro determines whether drug interacts with target’
‘in vivo tests pharmacokinetic properties’
‘in vivo identifies problems which cannot be picked up in vitro’

Question 9

Test validity

Answer 9

automation and easy detection are highly desirable

High throughput screening (HTS)

Question 10

Robotics

Answer 10

automated testing of many compounds (compound
library) on a large number of targets
Several 1000 compounds tested in 30-50 biochemical tests
These tests need to be easily measured:
1) Colour change
2) Radiolabelled ligand - may not bind to receptor if test compound is already bound (has a higher affinity)

Question 11

Conclusion so far

Answer 11

• Increased selectivity = reduced side effects
• in vitro and in vivo testing (+ clinical testing)
• HTS is preferred

Question 12

What happens once drug type, drug target and the testing

system have been determined?

Answer 12

We need to establish a lead compound
- a compound showing the desired pharmaceutical activity
(a starting point)

Question 13

Sources from which the lead compound can originate….

Answer 13

1) Natural product screening
2) Medical folklore
3) Screening compound libraries
4) Existing drugs (Me too drugs)
5) Natures ligands / modulators
6) Combinatorial synthesis
7) Computer aided design
8) Serendipity
9) NMR data

Question 14

1) Natural product screening

Answer 14

• A rich source
• Most biologically active natural products are secondary
  metabolites
• Tend to be complex structures and therefore novel
• Generally hard to synthesize in the lab (two alternatives, either
  perform a biological extraction or simplify structure for
  synthesis)

Question 15

1) Natural product screening

What pools can we take from?

Answer 15

(a) Plant kingdom
(b) Microbial world
(c) Marine world
(d) Animals
(e) Toxins (venoms)

Question 16

1(a) Natural product screening - The plant kingdom

Answer 16

The plant kingdom - plentiful, rich, complex & varied
Morphine, cocaine, digitalis, quinine, nicotine etc. etc.
More recently, Paclitaxel, (Taxol®) - from the Pacific Yew Tree (a very effective anticancer agent)

Question 17

2) Medical Folklore

Answer 17

§ experimentation with berries, leaves & roots
§ local healer brews
§ often useless & dangerous
§ example of Placebo effect - state of mind, no real differences

Question 18

2) Medical Folklore -

Chinese herbal medicine

Answer 18

Chinese herbal medicine - clue for antimalarial agent
(artemisinin). Such herbal medicines may work through synergy.
In other words, the mixture acts together (many complex
structures and interactions) to generate a beneficial effect

Question 19

2) Medical Folklore - examples

Answer 19

• Morphine from the opium poppy - Ancient Egypt
• Reserpine from the snake-root plant - India
• Salicin from the willow tree - Medieval England
• Quinine from cinchona bark - Aztecs (S. America)

Question 20

3) Compound libraries - screening

Answer 20

• Compounds synthesized, but, not made it as far as the
market place. Therefore stored and used against new targets as they appear / as new tests are developed (on the
off chance that they are beneficial)
• Storage is usually catalogued based on functionality that is
present & will also include compound intermediates on
route to a more complex target molecule

Question 21

3) Compound libraries - screening - example

Answer 21

e.g. antitubercular agents, isonicotinaldehyde thiosemicarbazone

Isoniazid - is the synthetic intermediate, BUT more active than the target compound.

Question 22

4) Existing drugs (Me too drugs)

Answer 22

• Using drugs from competing companies as a starting point

- Modify the structure to avoid patent restrictions, yet with improved therapeutic properties.

Question 23

4) Existing drugs (Me too drugs) - examples

Answer 23

-e.g. Captopril as a Me too drug (an antihypertensive agent)