Overview Of Preclinical Research

Question 1

What are the 5Rs that are addressed in drug development?

Answer 1

Right target 
Right tissue 
Right safety 
Right patient 
Right commercial potential

Question 2

What is the definition of a drug target?

Answer 2

A drug target is one that a molecule binds to produce a desirable effect

Question 3

What are the main aims of pre-clinical/animal studies?

Answer 3

To provide information on safety and efficacy of a drug candidate before testing in humans

Question 4

What are in-vivo studies?

Answer 4

Experiments inside an inside living organism

Question 5

What are in-vitro studies?

Answer 5

Experimentations outside an organism in test tubes

Question 6

What are ex-vivo studies?

Answer 6

Experimentations of intact tissues/organs outside a living organism.

Question 7

What are in-silico studies?

Answer 7

Experimentations using computer simulation.

Question 8

What are some advantages of in-vitro procedures?

Answer 8

High throughput screening = screening of known compounds from libraries
Reduced cost
Less regulations

Question 9

Give examples of in vitro tests.

Answer 9

Cell line based training

• cell biology
• mechanism of action
• toxicology

Question 10

Give an example of in-vivo testing and its use.

Answer 10

Small animals

• For complex disease mechanisms
• Overall effects on intact living organisms
• Effect of other organ systems
• Pharmacokinetics
• Safety
• Mandatory before human testing

Question 11

What are the disadvantages of in vivo testing?

Answer 11

Highly regulated

Low throughput

Question 12

What is a cell line?

Answer 12

Is a permanently established cell culture that will proliferate indefinitely given appropriate fresh medium and space.

Question 13

What is the purpose of using in-vitro cell lines?

Answer 13

• Studying physiology, pathology and cell growth

- Alterations in the structure, function and genetic makeup of the cell under controlled environments

Question 14

What is the disadvantage of in-vitro cell lines?

Answer 14

Not reflective of the biology of living organisms

Question 15

What are the limitations of animal in-vivo models?

Answer 15

Not able to model all aspects of human disease
Even long term animal models are relatively short-term compared to the course of human disease
Species differences in biology
Animal studies have limited genetic diversity and they are carried out under controlled environmental conditions

Question 16

What are the 3Rs of animal research?

Answer 16

Replace - animal studies with non-animal studies
Refine - minimise stress of study animals
Reduce - as few animal studies as required and necessary

Question 17

What are the limitations of in vivo studies?

Answer 17

Results have limited replicability in humans
Due to:
Interspecies differences
Environmental stimuli - lab conditions may differ from natural environment

Question 18

What is a genome?

Answer 18

An organisms complete set of DNA

Question 19

What is genomics?

Answer 19

Study of the Genome, including Gene–gene and gene-environment interactions

Question 20

Where can new drug targets be found?

Answer 20

Genomics & bioinformatics
Genetics - human mutation data linked to disease
Phenotypic arrays
Clinical precedent - information from existing drugs

Question 21

What is genetics?

Answer 21

Hereditary

Question 22

What is epigenetics?

Answer 22

Heritable changes in gene expression without changes to genome

Question 23

What is bioinformatics?

Answer 23

An interdisciplinary science of storing, retrieving and analysing large amount of biological information

Question 24

What is pathway analysis?

Answer 24

Finding out if the differentially expressed genes are associated with a certain biological process/molecular function.

Question 25

How are drug targets found through genetics?

Answer 25

Human mutation data linked to disease

Question 26

Phenotype studies for finding drug targets.

Answer 26

In vivo and in vitro phenotypic models
Neutralising antibodies/ gene knockdown
Clinical compounds/ drugs

Question 27

Clinical precedent in discovery of drug targets.

Answer 27

Through information from existing drugs

Question 28

What are the 2 steps in target validation?

Answer 28

Reproducibility of drug-target effect

Confirming drug-target effect

Question 29

What is lead generation?

Answer 29

Identify drug compounds to bind to a target that is validated.
High throughput screening using compound libraries

Question 30

What is high throughput screening?

Answer 30

HTS is a large compound libraries screened against an isolated target in a system.

Question 31

What is fragment screening?

Answer 31

Screening of small fragments of compounds to pick up low affinity binding sites that can be built upon

Question 32

What is rational subset screening?

Answer 32

Identification of chemical family/class known to hit target to increase hit rate
Modification of existing active molecules through the knowledge of pharmacokinetics and toxicology

Question 33

What are the aims of safety pharmacology?

Answer 33

Early detection & elimination of hazards
Risk assessment before first in human studies
Risk management and mitigation during clinical development

Question 34

What is on-target toxicity?

Answer 34

Toxicity related to the primary mechanism of action.

For example; if a drug is designed to affect GPCR, this would result in the drug hitting the G protein too hard

Question 35

What is off-target toxicity?

Answer 35

Toxicity is not predicted
= secondary affects
Drug has secondary affects on calcium channels for example.
Causing cardiovascular and neurological disorders