Lec. 21 - Drug Design 1 (Basic Research) Flashcards
In recent years, what has happened to the cost of developing drugs? And the output? Why?
Cost has gone up tremendously, while output has remained fairly similar.
This is because most of the “easy” drugs have already been found and developed
What’s a newly arising type of drug? What mainly makes up this group?
Biological drugs (mostly monoclonal antibodies)
What are the phases of drug development?
Drug discovery -> pre-clinical -> clinical trials -> FDA review -> Clinic
By how much are drug candidates whittled down during drug development at each phase
Drug discovery: 10 000 compounds
Pre-clinical: 250 compounds
Clinical trials: 5 compounds
FDA approval: 1 approved drug
What is current annual cost of drug development
> 90 billion dollars
In what way is Alzheimer’s an outlier to most disease trends?
It has been stubbornly difficult to find any treatment or cure for Alzheimer’s. We still have yet to find any truly effective drugs, as we don’t even really understand the pathophysiology
What is a new drug on the horizon for Alzheimer’s in 2021? What are some downsides?
Aducanumab ->
Monoclonal antibody injection that would clear amyloid fibers from the immune system before plaques are made, which would prevent neuroglia & neuron death.
Evidence is minimal, cost is enormous and daily injections take a toll on the quality of life.
Currently rejected in Canada, approved by the FDA
What are the 2 main reasons drugs get rejected during clinical testing?
Pharmacokinetics and lack of efficacy
What is happening to the number of antibiotics going to market?
Why is this the case?
Is there some new pressure that may change this?
Fewer and fewer introduced.
Not profitable for the pharmaceutical companies, as the drugs are only sold for a few weeks and not much money can be made.
Clinical trials:
How long do they take?
How much do they cost?
What’s the success rate?
10-15 years
Up to 4 billion
Only 10% of drugs make it to market
What are the top 3 most profitable conditions for pharmaceuticals to treat?
- Inflammatory conditions
- Diabetes
- Cancer
Name 3 chronic diseases that need research (due to expanding life spans)
- Alzheimer’s
- Parkinson’s
- Arthritis
What are the 2 types of arthritis
- osteoarthritis (wear and tear)
- rheumatoid arthritis (autoimmune disorder)
What are the 2 biggest killers today?
Cancer and cardiovascular disease
Goverment vs big pharma:
Who pays most for respective phases of drug development?
Gov -> pre-clinical work (often in funding university research)
PhRMA -> mostly clinical trials
What is generally the first step in drug development?
Understanding the pathogenesis of the disorder -> if you know the problem you can try and find a solution
Name 3 examples of drug targets
What are the most common targets?
- Ligand-gated ion channel
- GPCRs
- Enzyme
Generally, receptors and enzymes
What is gene therapy?
What’s an example of a success story using this approach?
A viral vector carrying a gene is added to a cell, the gene is then inserted into the nucleus. The gene encodes for a protein that was missing in a particular disease.
Cystic fibrosis (patients for whom their lungs lack a chloride channel) can be treated this way.
How does pre-genomics (3) differ from genomics (5) when studying the pathogenesis of a disease?
Pregenomics:
- Uniform disease description
- Patient homogeneity
- Universal therapeutic/treatment strategy
Genomics:
- Disease mechanism
- Disease heterogeneity
- Individual variation
- Patient risk assessment
- Targeted care
Why do we measure gene expression when studying the disease?
-Disease markers and drug targets:
Variation could suggest novel drug targets
-Response stimuli:
Environmental factors can often cause changes in expression
Describe microarray technology
DNA complementary to genes of interest laid out on solid surface
DNA from samples eluted over surface
Complementary DNA binds
Bound DNA detected by fluorescence
What’s the (simplified) path to drugs from genomics?
Genomics -> proteomics -> structural biology -> drugs
Describe the process of finding possible ligand candidates for your target.
Using compound libraries, we can screen thousands of compounds to find ‘lead compounds’.
These lead compounds are then tested in pre-clinical trials.
If one lead compound is found to work best, you make thousands of variations to said-compound and restart the process from the top (lead optimization).
How can combinatorial chemistry be used to help find possible ligand candidates for your target?
Allows to put different part of a molecule together to test out a bunch of possibilities
