Overview Of Preclinical Research Flashcards
Define preclinical research
Research that is conducted before clinical trials
Drug target
A target that a molecule binds to produce a desirable effect
Pathway analysis
Network of proteins associated with a particular disease
Phenotype studies
Studying the morphology, migration and invasion capacity of cells (disease cells generally move faster from one place to another and invade surrounding tissue)
To find new drug targets what happens?
Compare gene/protein expression between normal vs disease
Pathway analysis
Phenotype studies
Companies tend to concentrate on developing drugs for diseases that are prevalent in developed nations, why?
Strong focus on diseases like cancer, flu, depression
Developing countries don’t have resources or funding in place
Why is malaria an exception? For developing drugs in developed nations?
Due to tourism and spread of malaria to southern States of US
Screening libraries
Compound libraries
Need to find a hit’ candidate drug
High through put and less resource intensive than phenotypic approach
High throughput screening
Large number of compounds are tested very quickly in anautomated fashion
Lead optimisation is when?
Medicinal chemists make changes to chemical groups of compounds to make it more selective, potent, effective etc
Primary screen
High through put screening of hundred of thousands of compounds to identity active compounds against target
Compound screening cascade
Primary screen
Secondary screen
Lead optimasition - medicinal chemists make changes to chemical groups ofcompounds to make it more selective, potent, elective etc
Safety and toxicity
Efficacy
Clinical trials-only one
Target selection and validation
Primary screen, secondary screen, leads optimisation, safety and toxicity, efficacy
In vitro
Experiments outside an organism in test tubes
Advantages, of in vitro
High throughput screening
Reduced costs
Less regulations
In vivo
Experiments inside an intact living organism
Disadvantages in vivo
Highly regulated
Low throughput
Not able to model all aspects of human diseases
Long term models relatively short term
Species differences in biology
Animal studies have limited genetic diversity
Carried out under controlled environments
Ex vivo
Experiments of intact tissue/organs outside a living organism
In silico
Experiments using computer simulation
Cell line is a permanently established?
Cell culture that will proliferate indefinitely given appropriate fresh medium and space. They are immortalised
Importance of cell line
Important for studying physiology, pathology and cell growth
Tell us about alterations in structure, function and grout makeup of the cell under controlled environments
Cell line limitations
Not reflective of the biology of living organisms
How is cell line established?
Cells extracted from humans or animals
Introduction of an aberration with the appropriate space and cellmedium
Aberration
An abnormality of the chromosome number in a cell
Lead optimisation is a process by which?
A drug candidate is further improved after an initial lead compounds is identified
Lead optimisation aims at enhancing the mostpromising compounds how?
Improve effectiveness
Reduce toxicity
Increase absorption
Why does drug development fail?
Don’t work-efficacy
Not safe -toxicity
Lead optimisation: lipinski rule of 5
Molecular weight <500
Solubility log p<5
< 10 hydrogen bond acceptors
<5 hydrogen bond donors
Therapeutic index is a measure of?
Drug safety
Higher therapeutic index
Bigger window of drug effect
5 Rs
Right target
Right tissue
Right safety
Right patient
Right commercial - defining the right commercial value and future viability
Absorption
Movement of drug from its side of administration into the blood
Distribution
Movement of drugs throughout the body
Metabolism
Transformation of pharmaceutical substances into metabolites
Excretion
Removal of pharmaceutical substances from the body
Target occupancy
Measures the degree to which the test drug occupies its target in the tissue/animal
Toxicology testing is required to?
Demonstrate that drugs are safe before they can be given to humans
In vitro toxicology provides an early indication of?
The potential for some kind of toxic effects, allowing a decision to terminate a development program before spending too much money
Characteristics of in vitro toxicology
Less expensive to ran than in vivo
Faster than in vivo
Modelling in vitro toxicology study:
Drug in interest and control added to cells
then add SYTOX to drug Petri dish ( if cells die, then cells turn green)- if killing normal cells, then the drug is toxic
High throughput screening
Is a drug discovery process that allows automated testing of large numbers of chemical and/or biological compounds for a specitio biological target.
They accurate target analysis, as large scale compound libraries canquickly be screened in a cost effective way
What information does “target occupancy” show in the development of a drug?
It shows evidence that the target site is occupied by the drug candidate to the intended extent
