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Flashcards in Drug Discovery Deck (22):

What is High throughput screening (HTS)?

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


What is a compound library

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 the rule of 5)


What is the Rule of 5

Desirable properties for an active drug:
- Small molecular weight (<10)


What is the process of rational drug design

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


Why is the HERG channel important in drug design?

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


How was the drug 'Maraviroc' developed?

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!


What are the stages involved in drug discovery

Target discovery
Lead discovery
Lead optimisation
Preclinical development


What are the stages involved in drug development

Preclinical/clinical development.
Marketing and sales


What are the advantages of fragment screening?

Smaller libraries cover large chemical space
Potential to produce better fitting compounds


What are the disadvantages of fragment screening?

Crystalline structure required
Specific/specialised assay technology used


Give some examples of screening assays used in HTS

Radioligand binding assays
Alphascreen assay
Functional cell based assay (using calcium sensitive dyes)
Beta-arrestin assay


What is the role of DMPK in drug discovery

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


What does DMPK stand for

Drug Metabolism and PharmacoKinetics (DMPK)


What are the most commonly targeted molecules

Ligand gated ion channels
Nuclear receptors
EC2 transferases
Ion channels


What is fragment screening

Screen smaller fragments of the target to try and build up efficient leads (potency not important). Can add together to make a potent drug.


How does a functional cell based assay work (calcium sensitive dyes)

Fluo3 fluoresces when bound to calcium
Fluo3 loaded into cells
GPCR (linked to Gq protein) activated. Causes calcium release. Measurable through fluorescence screen.


How does a beta arrestin assay work

Complementation assay.
N-terminus of GPCR is mutated.
When beta-arrestin binds, a substrate can cause a chemiluminescent signal.
Specialist cell required.


What does the process of highthroughput screening involve

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


What is lead optimisation

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


What are the 4 phases of lead optimisation

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


What is the Caco-2 assay used for

Specific cell line that acts like the gut lining. Shows if a specific drug can travel through the GI tract (tests absorption)


How is drug metabolism tested in vitro (model)

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