MP2. Drug discovery

Question 1

pre-requisites of modern drug discovery?

Answer 1

-understanding of disease (Cellular mechanisms, biochemical pathways involved)
-Identification of a ‘target’ for the drug
-Simple assay to detect drug-target interactions in vitro (ex: fluorescence, change in colour, etc…)

Question 2

in vitro meaning?

Answer 2

outside a living organism (ex: in a test tube or culture dish)

Question 3

what do you need to know about a ‘target’ for a drug?

Answer 3

-Known chemical (and 3D) structure
-Known cellular and biochemical effects of drug binding to the target

Question 4

stages of drug discovery?

Answer 4

1) Screening a compound collection
2)Finding ‘hits’
3) finding ‘lead’ compounds
4) Finding ‘New drug candidates’
ONE NOTE

Question 5

Describe drugs that come from natural products

Answer 5

-Molecules from plants, animals, microorganisms,…
-Huge potential! (only a tiny fraction of living species has been explored)
-In specialised companies (too expensive/risky for Big Pharma)

Question 6

Describe drugs that come from compound libraries

Answer 6

-Huge collections of compounds synthesised previously for other targets or diseases
-Large numbers of new compounds (1000s) synthesised by ‘combinatorial chemistry’
ONE NOTE

Question 7

Where can compound collection come from?

Answer 7

-natural products
-compound libraries
-computational simulations

Question 8

Describe drugs that come from computational simulations

Answer 8

-Modelling of the interactions between ‘virtual’ compounds and the target by powerful computers
-Best ‘virtual’ compounds are then synthesised and screened
-Most important approach nowadays (cheaper!)

Question 9

How are compounds screened for activity?

Answer 9

-‘High throughput screening’ (HTS)
-1000s compounds tested at the same time
-Robotic instrumentation
-Rapid results obtained

Question 10

how are the ‘lead’ compounds selected?

Answer 10

-must be potent (active at low concentration) as lower doses will be needed in patients
-must be selective (low interactions with other targets) as lower risk of unwanted side effects
-must show ‘drug-likeness’

Question 11

what is ‘drug-likeness’?

Answer 11

-Correct physico-chemical properties
-Correct ADMET

Question 12

Describe correct physico-chemical properties

Answer 12

-Low molecular weight (<500 kDa)
-Hydro-lipophilicity balance
-Solubility in water/buffers
-Chemical stability
-Other properties… extra tests are performed on the ‘hits’/’leads’ (solubility, stability, etc…)

Question 13

Describe correct ADMET

Answer 13

-Absorption
-Distribution
-Metabolism
-Excretion
-Toxicity
(for drugs taken orally)
ONE NOTE

Question 14

Why is ADMET important?

Answer 14

-Absorption: drug must get into the body
-Distribution: drug must get into the correct organ or tissue
-Metabolism: drug must not be transformed into another chemical entity to a too large extent (unless it is a pro-drug)
-Excretion: drug must not be eliminated too quickly
-Toxicity: drug must be safe

Question 15

How are ADMET properties evaluated?

Answer 15

-Absorption: transport across a layer of intestinal cells (Caco-2 model)
-Distribution: binding to serum albumin, interactions with transporter proteins
-Metabolism: chemical stability in presence of liver cell extracts (microsomes)
-Excretion: not tested! (human kidney models are expensive!)
-Toxicity: no cell death, no mutagenesis on cells from different tissues (ex: blood, heart, muscles, etc…)