Theme 3 Lecture 10

Question 1

Plant drug basd origins (DIGOXIN)

Answer 1

Many drugs originate from plant based origins such as foxglove DIGOXIN 1775
Then full structural analysis was 1962

Question 2

Ephedrine(more potent and less toxic)

Answer 2

Ephedrine lead to amphetamines and methylphedite which is used to treat ADHD.
These other compounds are usually more potent and less toxic

Question 3

Morphine-meperidine and fentanyl

Answer 3

The tertiary alkyl amine for fentanyl is 4 atoms away compared to morphine

Question 4

paclitaxel/Docitaxel

Answer 4

Potent anticancer drug found via phenotypic screening from a pacific yew tree.

This lead to Docitaxel which prevents tumor growth, used in prostate cancer.

Question 5

Why is screening of plant extracts a slow process(solvent, screening, time and conc)

Answer 5

Heat organic solvent and then purify the extract.
Then its screened, but contains many compounds and you have to screen at each level
Time consuming to solve the chemical structure
Also you dont know the conc of the extract.

Question 6

Why are plant based drugs important(vincristine)

Answer 6

Show high structural diversity and drug like properties e.g. vincristine acts to a different site a paclitaxel but is still an anticancer drug.

Question 7

How do microbes and higher animals contribute to drug discovery?(penicilin)

Answer 7

Penicilin G was derived from mould and the cephalosporin b-lactam antibiotics are also microbial (fungal) products.
cephalosporin c was then isolated to make cefotaxime(BROAD SPECTRUM ANTIBIOTIC)

Question 8

Doxorubicin anticancer drug(derived from a soil fungus)

Answer 8

Potent but causes cardiotoxicity.
Semi-synthesis used to eradicate this by changing the ester lactone to amide lactam
Thus improving metabolic stability

Question 9

what are the four types of naturally occuring sources of hits and leads

Answer 9

 Plants (for example, paclitaxel isolated from the yew tree)
 Isolated from soil fungus Microbes (for example, doxorubicin peucetius )
 Higher animals (for example, ziconotide isolated from cone snails)
 Natural ligands (for example, cimetidine derived from histamine) Streptomyces

Question 10

What role do natural ligands play in identifying hits and leads? (natural binding)

Answer 10

Once bound, the new molecule may either give a similar response to the natural ligand – a disease where a deficiency in the natural ligand is present or inhibit the effect of the natural ligand – a disease where the disorder is caused by over activity of the enzyme or receptor

Relies on previous knowledge

Question 11

Example of a natural ligand (histamine and cimetidine) and 5HT

Answer 11

The natural ligand is histamine and causes gastric acid secretion whereas the analogue cimetidine doesnt the opposite.
Another example is 5HT receptors agonists and then sumatriptan is a 5HT antagonist

Question 12

HIV Protease role

Answer 12

Cleaves s1 pocket between proline and phenylalanine
Then the secondary alcohol mimics the transition state of the cleavage and binds with high affinity.

Question 13

Azidothymidine (AZT)

Answer 13

Anticancer to HIV drug

Question 14

Imatinib and nilotinib

Answer 14

Both compounds bind in the same active site, however nilotinib is more potent

Question 15

Sildenafil

Answer 15

Was used to treat angina, then was found to be a PDE5 inhibitor in erectile tissues of males, so that was the new potential drug target.

Question 16

Pros and cons of natural ligands

Answer 16

A lot a known about how the natural ligand fits
cons= can be too similar to the original ligand causing side effects.

Question 17

What are the advantages of a drug discovery programme based on a clinical
observation?(unexpected benefit of medication)

Answer 17

(unexpected benefit)
If the drugs is already working on patients, that means it can be discovered faster than other processes, if not showing toxicities and its efficacious