L4 + L5 Searching for new 'lead' molucules DT

Question 1

one lead compound can generate drugs in different therapeutic classes. Give an example

Answer 1

Prontasil (antibacterial) produced:

• Carbutamide (anti diabetic)
• Furosamide (loop diuretic)

This was known as the sulphonamide dynasty

Question 2

Lead molecules come from 6 main routes:

Answer 2

• Screening
• Natural Products
• Side Effects
• Metabolism Studies
• Serendipity
• Rational Drug Design

Question 3

Explain how screening works briefly

Answer 3

1) Select a therapeutic area and its biological target e.g a protein or glycoprotein
2) Choose and develop an assay either manually or by High Throughput Screening (HTS)
3) Choose molecules to screen - > analyse screen for hits -> develop ‘hit’ to lead (medicinal chem)

Question 4

State the different type of primary screens

Answer 4

• enzyme based assays
• receptor based assays
• biochemical based assays
• cell based assays

Question 5

how do enzyme based assays work + example

Answer 5

It consists of a donor and quencher.

• There is NO fluorescence if the enzyme is inhibited by the quencher
• There is fluorescence if quencher is lost
  e. g Gleevec (Imatinib) for Leukaemia

Question 6

how do receptor based assays work

Answer 6

consists of ligand and receptor.

If binding takes place there is fluorescence

If complex does not form there is NO fluorescence

e.g Iressa for breast cancer

Question 7

how do biochemical based assays work

Answer 7

using non/radioactive methods such as ELISA/ radio immunoassay

Question 8

how do Cell based assays work and what is their advantage/ disadvantages

Answer 8

homogenous cells are non radioactive
heterogeneous cells are radioactive

Advantage: Cell based cytotoxic drugs are detected and eliminated at the outset

Disadvantage: requires high capacity cell culture facilities and were complex robotics to controlling incubations.

Question 9

In Vivo assays. What’s that? e.g?

Answer 9

Putting the drugs in animals and embroy’s. e.g zebra fish

Question 10

Name a plant and what drug it produced

Answer 10

Foxglove is the source of digoxin

Question 11

Name a bacteria and what drug it produced. What is this an example of?

Answer 11

Penicillin made by Penicillium Notatum. This is an example of Serendipity!

Question 12

Animal studies produced what?

Answer 12

Premarin for treatment of menopausal symptoms was obtained from pregnant mare urine

Question 13

Side Effect studies produced what

Answer 13

Sildenafil antihypertensive produced an ADR for erectile dysfunction

Question 14

Metabolism studies produced what?

Answer 14

Temazepam, a metabolite of diazepam (anxiolytic) but is more polar so faster effect and shorter duration of action. Thus given as an agent for insomnia instead

Question 15

Rational Drug design method examples

Answer 15

Structural biology
Screening
Molecular Modelling
Synthesis