Drug Discovery And Development Flashcards
What occured in the rinderpest cattle 1709
Major outbreak in Western Europe
Wiped out most of the cows at that time
What is rinderpest
Major viral disease
Causes fever, anorexia and eye discharge
What happened in the anthrax outbreak 1712
Killed cattle quickly
Fatal bacterial disease
Humans can et the disease
Is anthrax used as a biological warfare agent
Yes
What happpend in the 1715 foot and mouth disease outbreak
Contagious viral disease
Blisters, fever in cloven hoofed animals
What is the one health initiative
Recognises the inter-relationship between animal health, human heath and environment health
Wh was the one health initiative made
This because they all link together. If environment is affected it effects humans animals as we eat animals
Where did drugs originally come from
Herbs and potions
What did scientists do in the 19th century
Isolate and identify the biological activity components from herbs and plants
What is the 1st step to drug discovery
Identification of a disease where there is a need for a new drug
What are economical factors pharcuetical companies face when making a new drug
Developing a drug is complex - takes 10 to 15 years
Costs over 100 million pounds
Make sure there is good financial return for their investment
What is the problem in the western world when it comes to making new drugs
They aren’t as rich therefore drugs for new diseases do not get created unless the rich areas take notice and create the drug
What is the issue with drug making and the veterinary world
Not a lot of money in veterinary mediciene compared to human mediciene
What are the approaches o drug discovery
Bo-assay based
Target based
What is bio-assay based drug discovery?
Develop compounds to use against the disease to see if they’re active at killing the biological compound.
What is target based drug discovery
Identify the disease and then the target - receptor, enzyme etc
It synthesized agonists, antagonist or inhibitors against the except or/enzyme of the disease
What is the bioassay-based drug discovery method
Raw material - crude extract
Extract compounds using solvents
Test crude extract on bioassay to see if the crude extract shows potency and biological activity
Biologically evaluate the compounds showing biological activity using mass spectrometry
Medicinal chemiss then modify the compounds to make a more potent and selective drug
Clinical trials - if new drug gets through clinical trials it can then be licensed and marketed
What is the right bioassay for bioassay drug discovery?
Need to choose right bioassay - important to success to drug research programme
Needs to be quick and simple cant test compounds
Tests should be done on enzymes, tissues and isolated cells
Suitable biological assay - antimicrobial assay
What is artemisinin
Traditional Chinese medicene
Herbal plant
What is artemisinin effective against?
It was active against the strain of malaria that north Vietnam where facing in 1972
What is cephalosporins
Derived from a fungus found in sees in Sardinia
Looked at water and noticed that there was a clearing of turbid water
This then created the antibiotic cephalosporin
What created the drug hypertension
Venom from jaraca
What drug comes from teprotide venom
Captopril
What are chemical extractions
Extract compounds from material
What do you do in chemical extractions
Take plant and grind it in the solvent and look at the components in the solution you can use more than one solved to measure polarities in the plant
What is semi-purification
Removal of sugars and amino acids
Why do you remove sugars and amino acids from plants
We need to know if something is working due to the components of the plant and not the sugars in the plant
What happens during screening for biological activity
Once biological activation occurs you purify that compound more and separate into fractions and look at each fraction to see which one shows biological actity
What is purification
Separation and purification of individual compounds from the extract, screening for biological activity and purify using chromatography
What chromatography do you use if compounds are non polar
Normal phase chromatography
What chromatography do you use if compounds are polar
C18 reverse phase chromatography
What is preclinical testing
Biological evaluation in vitro and in vivo - identification of mode of action
Individual purified compounds can be tested in vitro assay and in vivo assays to identify the active components
What is high performance liquid chromatography
Giveees molecular weight and forums
Compound can be broken into fragments that can build up to make the molecule
Sensitive method - you can use nano-grams of the particle
Doesn’t tell you the carbon/hydrogen frame work
What is nuclear magnetic resonance spectroscopy
Gives the carbon framework of molecular and environment of the hydrogens
Gives information on the shape of the molecule
Information on how the compound binds to its target
Need 1 milligram for it to work
What is proto NMR
Tells us the environments of the hydrogens in the molecule
Usually locate double bonded hydrogens
What is cosy NMR
Find out which hydrogens are held by 3 bonds
What is NOESY nmr
Look up at hydrogens close up in space to other hydrogens - gives shape of molecule
What is HSQC NMR -
tells us which hydrogen is bonded to which carbon
What is HMBC NMR
Tells u what hydrogen is connected to carbon through 2-3 bonds
What is SARS
Structure acitvity relationships
What does SARS do
Identify which parts of the molecule are important for activity
How do you identify which parts of the molecule are important for activity in SARS
Changing each functional group of the molecule and investigate how it affects the way the molecule acts.
What drug do we aim for
A drug with god selectivity and no side effects
Or little to no side effects
What do they look at in clinical trials
Drug absorption
Distribution
Metabolism
Excretion
Efficacy
Dosage
Toxicity
What are the process of drugs in the body
Drug is administered
Drug is absorbed
Drug is now in systemic circulation
Drug gets distributed to tissues or he site of action
Drug is metabolised or excreted
Drug site of action creates a pharmological effect which creates a clinical response which can be efficacy
What is pharmokinetics
Where drugs go and what happens to it
What are pharmacodynamics
What does the drug do we it reaches the site of action
What is an effective dose
Dose or amount of drug that produces a therapeutic response
What is efficacy
Ability of the drug to elicit a response when it binds to the receptor
What does veterinary medicenes need
A marketing authorisation
What animal medicines not need a MA
Medicenes for small animals used as pets
Aquarium animals
What drugs need a MA
Antibiotics
Psychotics
What medicines with a MA need
A MA number
Should carry the symbol vm on packaging and printed material
What are the advantages of natural products
Novel structures - novel molecules
Disadvantages of using natural products
Impossible to synthesize certain materials
Some atrial moprducts are available in small amounts
Takes years to synthesize drugs
Example of drug that takes years to synthesize
Palitaxal - taken from bark of taxis brevoila - non renewable as tree got chopped down
They now use needles of the tree but takes 10 years to synthesize
What is the top down method
Candidate drugs screened for effect on phenotype
What does the top down method screen
Whole animals, organs or cells
What are the advantages of top down
Directly reliant to the disease if we have a good animal/experiemntal model of the disease
What is top down screening based on?
Screening for phenotypic changes relevant to treatment of disease
Why is top down method called top down?
Your testing at the most complex level and dining out what the biochemical target is
Disadvantages of top down methods
Very low throughout and cant test many compounds
What is the bottom up method
Candidate drugs tested for effect on biomechanical target molecule
What targets do bottom up test on
Receptors, enzymes dna
What is bottom up based on
Screeening of libraries or structure based design
What is the early essential step of bottom up procedures
Identification and validation of biomechanical target - protein dna -
What are the advantages of bottom up
Know the target
Get the structure of target
If you have structure - structure based design can be done
Disadvantages of bottom up
Although you find a target you dont know if it is valid or not
What is target identification and validation - bottom -up
Coming up with a good target to identify
Validation - making sure it is the right target
What is hit generation - bottom - up
When you evaluate hit compounds more and test various parameters
Bottom up process or target based drug discovery
Target identification and validation
Hit generation
Lead discovery and de novo synthesis
Lead optimisation
Preclinical tests
Clinical trials
Licensing and marketing
What is lead optimisation - bottom uo
Look at strucutre acitvity relationships and improve reactivity of the drug to make it more potent and selective
What does validation of target ensure
That if the drug binds to the target, the desired phenotypic change is achieved
What is the first step in drig discovery
Identify the target and validate it as its essential for target based bottom up drig discovery
What is a target in drug doscbery
A molecule in the body which is usually a protein which is associated to a particular disease pathway, or modified and could be addressed if we get the drug bound to the target to treat the disease
What happens if you try to inhibit an enzyme
If you inhibit a whole enzyme there are chances you can inhibit every pathway the enzyme is associated too which leads to on target toxicity
What is the method used before we test the design of a new drug
Identification
Assessment
Validation
What is identification
Understanding where the drug comes from and how it works
Biochemical pathways
Signalling pathways
What is assessment
Assess the target
Need to assess certain things before making the drug
Drug ability - success rate? Can we get a drg to bind to the target selectivity
What is validation
Making sure if we binge a drug to the target we actually get the outcome we want
Proving that all the steps done before this process will give us the outcome needed
What is knock-down.knock-out/Sirna
Ways to validate drugs - reduce amount of target proteins in the cells
What is knock-in/over expression
Add more copies of the gene for the protien target, does the disease get worse
What is drugabilit
Will it be possible to design a drug to bind to a target
Is structure available
Is it crystal or NMR
Where is the binding site
Why are broad fat eaturls - hydrophobic - sites not good
Drug cant bind to the compound
What do you have to think about when it comes to selectivity
Is binding site exclusive to this enzyme
That al the kinases bind atp
These two issues cause selectivity to be really hard
What is on-target selectivity
Toxicity resulting from the drug binding to the intended protein target
Unintended consequence - down regulation of the target n the cell
What is off target toxicity
Toxicity resulting from the drug binding to other protein targets in the cell
Can be addressed by design of drugs which are more selective for the target protein
Why do we need to sign dual set inhibitors and extend outside the active site
Use strucutre of biochemical to build inhibitor molecule to recognise the features of inside and outside section of the active site to create more potency and selectivity
What are the drug targets of bacterial cells
Enzymes
DNA/rna
Ribosomes
Cell walls
Polymyxins
Once we have a validated target what’s next
Identify hit compounds which bind to the target as inhibitors, agonists, or antagonist through target screening
Why do you need to design compounds using the strucutre of the target
Drug needs to fill up the space of the active site otherwise it will be ineffective
You can do this with computer models and make 3D strucutres of the target protein and the drug
