Drug Discovery and development

Question 1

What is High throughput screening (HTS)?

Answer 1

A method that involves using a biological assay to identify mechanisms of action without knowing the structure.Puts different structures with the drug target and uses an assay to test if novel molecules bind to the target

Question 2

What is a compound library

Answer 2

A collection of structures that can be used in High throughput screening. A good library is full of representative compounds (not just series molecules), and lead like (follow RO5)

Question 3

What is the Lipinski Rule of 5

Answer 3

Desirable properties for an orally active drug 
MW < 500
LogP < 5
HBD < 5
HBA <10

Question 4

What is the process of rational drug design

Answer 4

Generate a model of the target receptor/enzyme.Use this to build the drug to fit the gap.
However, doesn’t always work because proteins are flexible, and this doesn’t account for induced fits

Question 5

Why is the HERG channel important in drug design?

Answer 5

Drugs that block the HERG channel can cause ‘Torsades de Pointe’, a drug induced arrhythmia. This can cause death by ventricular fibrillation.

Question 6

How was the drug ‘Maraviroc’ developed?

Answer 6

It is a GPCR (CCR5) antagonist (Go/Gi coupled).
CCR5 cell line used with a displacement assay to find a suitable molecule.
First molecule was an agonist, so structure changed so drug was viable with no side-effects.
Improved structure was sent to other drug companies to test against their compound libraries, and was deemed safe.
Tested in animals, and gave good results. TAH DAH!

Question 7

What are the stages involved in drug development

Answer 7

Preclinical/clinical development.
Registration
Marketing and sales

Question 8

What are the advantages of fragment screening?

Answer 8

Smaller libraries cover large chemical spacePotential to produce better fitting compounds

Question 9

What are the disadvantages of fragment screening?

Answer 9

Crystalline structure requiredSpecific/specialised assay technology used

Question 10

What is the role of DMPK in drug discovery

Answer 10

Potential drugs are selected with DMPK properties appropriate to the intended drug target

Question 11

What are the most commonly targeted molecules

Answer 11

GPCRs
Ligand gated ion channels
Nuclear receptors
EC2 transferases
Ion channels

Question 12

What does the process of highthroughput screening involve

Answer 12

Test compound library
Retest positives (to weed out false positives)
Assess responses at different concentrations
Purify compounds and assess
TAH DAH! confirmed hit compounds

Question 13

What is lead optimisation

Answer 13

Transforming a biologically active compound into a clinical candidate. Involves optimising good bits, confirming activity in model organism and reducing side effects

Question 14

What are the 4 phases of lead optimisation

Answer 14

1a - activity/solubility/selectivity
1b - in vitro ADME
2 - in vivo ADME/activity
3 - safety

Question 15

How is drug metabolism tested in vitro (model)

Answer 15

Liver microsomes (contains phase 1 and 2 enzymes; requires co-factor supplements)
Liver hepatocytes (expensive)

Question 16

What are the desired properties of a fragment for use in fragment screening

Answer 16

Rule of 3:

MW

Question 17

What is ligand efficiency

Answer 17

LE = [change in Gibbs] / [number of non-hydrogen atoms]
or
LE = 1.4(-Ln IC50)/ [number of non-hydrogen atoms]

Question 18

What are the pros of fragment screening

Answer 18

Smaller library; large chemical space
Could produce better fitting compounds with more effective binding
Better starting point for DD

Question 19

What are the cons of fragment screening

Answer 19

Fragments have low potency
Specific/specialised assay needed
Crystal structure needed

Question 20

What are the stages involved in Drug Discovery

Answer 20

Target discovery
Lead discovery
Lead optimisation
Pre-clinical / clinical development (stage 1-2a)

Question 21

How is teratogenicity tested for in vivo and what are the limitations

Answer 21

Animal studies. Daily dosage during early stages of pregnancy. Assess any abnormalities that occur.
Limitations:
Time consuming, species differences, developmental differences, nutrition

Question 22

How is teratogenicity tested for in vitro and what are the limitations

Answer 22

Embryo culture/stem cells used in toxicity assays.
Limitations:
False +/- ves. Drug may be metabolised to a tetragen in vitro. PK may exclude embryo from exposure to toxic concentration

Question 23

What happens in phase 1 clinical trials

Answer 23

Safety and tolerance tests (MTD, etc)
50-100 volunteers
PK/PD + dosage studies

Question 24

What happens in phase 2 clinical trials

Answer 24

Dose-efficacy relationship (IC50, EC50, MTD/C etc)

400-800 patients

Question 25

What happens in phase 3 clinical trials

Answer 25

Two successful trials required for marketing approval.
Large patient group - 300-3000
Measures efficacy in target indication (double blind randomised trials, placebo/active controls)
Establishes long term safety/efficacy

Question 26

What happens in the approval/registration phase of Drug development

Answer 26

Data collected to make a regulatory submission document (animal/human, safety, etc)
Approval time ~ 18 months…….. (FDA, EMEA, etc)

Question 27

What happens in phase 4 clinical trials

Answer 27

Monitoring efficacy and costing. Identify other uses for drug/ side effects etc.
May cause market withdrawal or restrictions

Question 28

Define biomarker

Answer 28

A biochemical feature/process that can be used to measure the progress of a disease or the effects of a treatment using non-invasive procedures

Question 29

Define translational biomarker

Answer 29

Common biological/biochemical measures that can be made in animals and humans. Useful to test efficacy, PK, safety.

Question 30

How can translational biomarkers be applied to clinical development

Answer 30

Can be used in phase 0 trials (10-15 patients, sub-therapeutic dosage, Pk/PD relationships noted, to confirm predictions). Will give a go/nogo decision early on. Non-invasive.

Question 31

How might biomarkers be used in the future

Answer 31

Could be used to determine personalised medicine (e.g. breast cancer: ER +ve, HER2 overexp, BRCA1/2 mutation).