L22 Drug Design 1: Basic research Flashcards
What questions need to be answered before drug approval by reputable government agency
Does the drug work
What are the side effects
How does it compare to what’s already available
What do risk-benefit analysis’ assess
do benefits outweigh the side effects? how do these risks and benefits compare to drugs already on the market
What are the current major killers?
cancer and heart disease
What are some drug designs for the future?
antibodies, cytokines, cells, etc.
personalized therapy
What is pathological research
research basic problems, abnormalities behind disease
What is pharmacological research
how certain drugs and potential drugs can modify the course of a disease
TF: Drug companies spend the second most money on research, following computer software and services companies
False, drug companies spend the most $$$
Why is it getting more expensive to research new drugs?
all the easy ones have already been researched
What is the current Toal cost of drug development and testing per year?
> 90 billion dollars
Why is Alzheimer’s disease so difficult to develop a drug for?
the basic pathophysiology/pathogenesis is unknown
What characterizes AD?
deposition of amyloid plaques in the brain which are associated with destruction of the brain
What’s Eli Lilly?
Flop company that developed a drug for AD ultimately proven to be useless compared to placebo during longer periods of testing
lost 1 billion dollars ouch
What is Aducanumab
a monoclonal antibody (MAB) that removes amyloid fibre via immune system before the amyloid plaques are even made (for AD)
minimal efficacy, expensive injections required for the rest of ones life
What are some reasons for drugs to be rejected in clinical testing?
-toxicity in animals
-high costs
-lack of efficacy
-pharmacokinetics
-side effects
Why are there less antibiotics being developed despite the arising antibiotic resistance problem?
they are not profitable
How much do clinical trials usually cost? How much time does it take?
$4 billion
10 years
Which drugs make the most profit (3)
- inflammatory conditions
- diabetes
- cancer
What are currently major selling drugs?
MAB for cancer
CV problems
skin problems (e.g. psoriasis)
What is preclinical research
it is the first phase of drug development (following the ‘idea’)
basic pharmacology and toxicology are looked into to see if the drug works, if it has any side effects/risks
What are current major challenges in healthcare?
-chronic diseases (e.g. AD, PD, arthritis)
-cancer
-CDV (MI, stroke)
-emerging infections and pollution
TF: government does most of the clinical research while industries (PhRMA member companies) focus on basic research
False, government funds bail research and some of the initial translation research in animals while industries do almost all clinical research (testing in humans)
Understanding og _ is at the core of drug development
pathogenesis
TF: drugs can be studied on individual cells
True
cell extracts can be used to study the mechanism of action of new drugs
Why is drug target identification considered the goal? What are examples of drug targets? What are the current most common drug targets?
Knowing the target allows for drug development
targets can be ligand-gated ion channels, GPCRs, enzymes, receptors, etc.
current drug targets are enzymes and receptors
What does the drug that treats HIV target?
HIV protease (enzyme) inhibitor
What are possible causes for side-effects
multiple control pathways present in the human body, drug target may be present in multiple tissues, disease may have multiple targets that must be acted on
Why are pharmacogenomics important for drug development
We try to select people who will respond to particular drug based on their genetics to avoid terrible side effects (some people may be more vulnerable)
genetic polymorhpisms related to pharmacokinetics and pharmacodynamics lets us know who shouldn’t be administered the drug
What causes cystic fibrosis
individuals are unable to make a particular chloride channel causing mucus buildup in lungs
How is cystic fibrosis treated
gene therapy
viral vector carrying new gene into cell inserts this gene into the nucleus of the cell. Cell can now encode the missing protein
What is a recent and successful example of gene therapy?
replacement of sickle-cell/thalassemia genes with normal RBC gene using CRISPR
TF: CRISPR is used for gene therapy
True
What happens during sickle cell disease
RBC are abnormally shaped resulting in them transporting fewer hemoglobins and thus less oxygen
What is pregenomics
disease description, uniform disease, patient homogeneity, universal
therapeutic strategy
What is genomics
disease mechanism, disease heterogeneity, individual variation, patient risk profiling, pharmacogenomics, and targeted care
TF: Environmental changes can cause changes in gene expression
True
What is microarray technology
DNA complementary to genes of interest is generated and laid out in microscopic quantities on solid surfaces at defined positions
DNA from samples is eluted over surface-complementary DNA binds
Presence of bound DNA is detected by fluorescence following laser excitation
what is angiogenesis
the growth of new blood vessels (around a tumour)
How do you go about finding what ligands bind to your target?
Combinatorial chemistry gives thousands of potential compounds that can be tested (compound library)
promising compounds are selected and further tested
What are “lead compounds”
compounds that are used during pre-clinical testing that have been screened from a compound library
if one is deemed useful during pre-clinical testing, it is optimized (make thousands of variations) and then tested
What is lead optimization
when a lead compound is used to make thousands of variations to find a compatible ligand
What is high throughput screening
testing thousands of compounds made in combinatorial chemistry
takes less time than manual screening
How many compounds can be screened per day when using robotics + bioinformatics
20 000 compounds per day
What are some possible test systems used during drug development
mammalian cells, microbes, human hepatocytes, microsomes, synthetic membranes, beads, etc.
TF: combinatorial chemistry is done in vivo
False, it is done in vitro
then you can move along to in vivo studies in animal models
What are the requirements for high-throughput screening
- suitable compound libraries
- assay method configured for automation
- robotics work station
- computerized system capable of handling the data
What are ways in which responses from ligand binding to target i.e. drug can be assessed
fluorescence, luminescence, enzymatic, radioactive, immunological
What is ‘automated ligand identification system’
a way of identifying potential ligands: target is mixed with a bunch of potential ligands. solution is then washed to see which ligands had the highest affinity via mass spectrometry
What animal has been used in a multitude of studies due to its nervous system and embryonic development
zebrafish
HTS (high-throughput screening) cannot evaluate: (5)
- bioavailability
- pharmacokinetics
- toxicity
- mutagenicity
- specificity
How are yeast cells used to assess mutagenicity of a compound
yeast cells have DNA repair genes that are expresses in response to mutagens that induce damage to DNA. coupling these DNA repair genes with luciferase and assessing fluorescence can help detect DNA damage
more fluorescence = more DNA damage = mutagen
How would you test for chemotaxis and metastasis
chemotactic factor on one side of the filer and see if that draws the cells from the other side
this allows to see if a drug is capable of blocking metastasis
Most new drugs are eliminated during which stage of drug development?
clinical development
What is bioinformatics
using softwares to aid in drug development and understanding go biological data
What is computational chemistry
branch of chemistry that uses computer simulations and theoretical methods to study and understand chemical systems. It involves the application of mathematical models and algorithms to simulate the behavior of molecules and analyze their properties.
TF: Computational chemistry was used to develop the drug that cures AIDS (HIV protease inhibitor)
True
What is Ibrutinib (Imbruvica)
a drug that blocks an enzyme that is over expressed in malignant B cells (chronic lymphocytic leukemia)
It was developed using computational chemistry
what do PCSK9 inhibitors do? What are they used for
PCSK9 inhibitors are used to treat atherosclerosis. They are MABs
it blocks the PCSK9 enzyme that is involved in degrading LDL cholesterol receptors which are responsible for decreasing cholesterol in circulation
PCSK9 inhibitor thus increasing the number of LDL receptors recycled back to the membrane and increases cholesterol clearance
The bridge between what 3 fields has increasing efficiency and speed of drug development
genomics, combinatorial chemistry, bioinformatics
What is biosimulation
a way of simulating pathogenesis and mechanisms of biological pathways implicated in diseases
useful for drug discover and minimizing side effects
How are monoclonal antibodies made
made from a combination of species (hybridomas): combination of mouse and human antibodies, variable regions derived from primates, or purely human antibodies
What are some strategies to avoid formation of anti mouse antibodies (4)
- chimeric antibodies (mouse variable region, human constant region)
- privatized antibodies ( chimeric with primate derived variable region)
- humanized antibodies (all human except antigen recognition site)
- transgenic mouse antibodies (fully humanized antibodies)
MABs have been used to treat…
rheumatoid arthritis, Crohn’s disease, cancers (B cell malignancies CLL, breast cancers), osteoporosis
How are MABs used to treat osteoporosis
the antibodies target osteoclasts which are responsible for breaking down the bone
How are MABs used to treat beast cancer
the antibodies target HER2 (human epidermal growth factor receptor 2)
What are some targets for MABs when it comes to tumours?
the tumour itself, its microenvironment, its blood supply
What is adalimumab used for
TNF (tumour necrosis factor) inhibition for treating autoimmune diseases like rheumatoid arthritis, psoriasis, Crohn’s disease
why is TNF (tumour necrosis factor) a big target for treating autoimmune diseases
it is found in many tissues and is important in immune resoinses
What is Infliximab used for?
rheumatoid arthritis
TF: over 90% of animal models are rodents
True
Which test can be used to look for mutants?
Ames test
DNA repair genes + luciferase test in yeast cells
What are the 4 steps in the first phase of drug discovery?
- find target
- find a lead
- optimize lead
- ADMET (absorption, distribution, metabolism, excretion, toxicity)
you can then file an application for a clinical trial
What is golden rice
rice infused with beta-carotene (vitamin A provitamin) that is isolated from beta-carotene gene in daffodils
to help fight against vitamin A deficiency
