Med Chem 2 Flashcards
Deciding upon a suitable test…
Bioassay - used to test drug candidates
- choosing the right bioassay (4 consideration)
1) Simple
2) Quick
3) Relevant
4) in vitro or in vivo
The advantages of in vitro testing…
1) Inexpensive
2) Easier to perform
3) Less controversial
4) Automated (often)
Other advantages to in vitro testing…
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
Potency
Potency - amount of drug required to achieve a defined biological effect
Efficacy
Efficacy - measure of how effectively an agonist activates a
receptor. Drug can have a high affinity for a receptor but a low efficacy
Advantages of in vivo testing…
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
Disadvantages of in vivo tests - on animal or humans
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)
In vitro vs in vivo
‘in vitro determines whether drug interacts with target’
‘in vivo tests pharmacokinetic properties’
‘in vivo identifies problems which cannot be picked up in vitro’
Test validity
automation and easy detection are highly desirable
High throughput screening (HTS)
Robotics
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)
Conclusion so far
- Increased selectivity = reduced side effects
- in vitro and in vivo testing (+ clinical testing)
- HTS is preferred
What happens once drug type, drug target and the testing
system have been determined?
We need to establish a lead compound
- a compound showing the desired pharmaceutical activity
(a starting point)
Sources from which the lead compound can originate….
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
1) Natural product screening
- 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)
1) Natural product screening
What pools can we take from?
(a) Plant kingdom
(b) Microbial world
(c) Marine world
(d) Animals
(e) Toxins (venoms)
1(a) Natural product screening - The plant kingdom
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)
2) Medical Folklore
§ experimentation with berries, leaves & roots
§ local healer brews
§ often useless & dangerous
§ example of Placebo effect - state of mind, no real differences
2) Medical Folklore -
Chinese herbal medicine
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
2) Medical Folklore - examples
- 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)
3) Compound libraries - screening
• 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
3) Compound libraries - screening - example
e.g. antitubercular agents, isonicotinaldehyde thiosemicarbazone
Isoniazid - is the synthetic intermediate, BUT more active than the target compound.
4) Existing drugs (Me too drugs)
- Using drugs from competing companies as a starting point
- Modify the structure to avoid patent restrictions, yet with improved therapeutic properties.
4) Existing drugs (Me too drugs) - examples
-e.g. Captopril as a Me too drug (an antihypertensive agent)
