Drug Discovery (Exam 3) Flashcards
What is the bulk of drug discovery?
preclinical and clinical studies
process of traditional drug discovery
target identification
target validation
lead identification
candidate optimization
preclinical
target identification involves
drug receptors
drug receptor
usually a protein
macromolecule component of a cell which a drug interacts to produce a response
challenges of drug discovery
proteome
large dynamic range
proteome involves
over 1 million proteins due to splice variants and post translational modifications
large dynamic range challenges
low abundance proteins
no amplification system
pharmaceutical proteomics
proteome approach to the interaction of drugs with biological systems
proteomics
study of protein properties on a large scale to obtain a goal, integrated view of disease processes, cellular processes and networks at the protein level
proteomes are
dynamic
why is proteomics important?
parallel analysis of multiple proteins
discovery of disease specific proteins
expression proteomics
quantitative expression of 1000s of proteins
2D gel/ image analysis central
approach to identify low abundant proteins
reduce complexity (purification)
enrichment (concentration)
specific proteins may be resident in
specific organelles
the conventional approach to separate out organelles
differential centrifugation - labor intensive
batch vs continuous
batch - have to make new batches, tedious
continuous - produce large amounts, don’t need to make batches
continuous flow - ultra centrifugation
material continues to be circulated
used in vaccine production
collect specific fractions along the way
experimental validation
organelle enrichment
proteomic profiling
protein identification
western blot steps
SDS polyacrylamide gel electro
protein blot on nitrocellulose
label with specific antibody
detect antibody and protein present
enrichment
fractions present can be used as a marker for organelles
can be used to isolate proteins
2D gel electrophoresis
charge (isoelectric point) and size (molecular weight)
can see a lot more proteins this way
when there is enrichment compared to no enrichment,
there are a lot more signals of proteins since enrichment can resolve lower abundant proteins
there is less noise from more abundant proteins
protein identification
2D gels –> digest and bioinformatics to identify
Post translational modified low abundance proteins
same aa sequence but different modifications
can be separated due to this
steps of discovery
- continuous flow centrifugation
- reduce complexity
- 2D gel
- mass spec
proteins typically function as
complexes
multi-protein complexes involved in
DNA replication
energy metabolism
signal transduction
___________ of protein-protein interactions occur in a cell
thousands
protein-protein interactions are essential to
most processes that take place in a living cell
protein-protein interactions occur because the interior of cells is
crowded
what is common upon binding in protein-protein interactions?
conformational changes
yeast two hybrid
insert bait gene protein alongside DNA for half of an activator protein
other half of the activator is inserted alongside DNA for random prey protein
yeast grows and protein interacts
what signals a match in yeast two hybrid?
the cell turns blue when the two halves of the activator proteins meet
whole genome two hybrid screens
construction of bait and target libraries covering entire proteome
automated screening for positives
most proteins are involved in
many interactions
protein microarrays
analysis of thousands of proteins at one time
types of protein microarrays
antibody arrayed
proteins arrayed
peptides
protein microarray process
high throughput analysis of proteins
proteins immobilized on glass chip
various probes are used
examples of protein substrates
polyacrylamide or agarose gels
glass
nanowels
protein attachment examples
diffusion
adsorption/absorption
covalent attachment
affinity
protein interactions examples
antigen-antibody
protein-protein
aptamers
enzyme-substrate
receptor-ligand
different _________________ must be used to study different interactions
capture molecules
probes interact with
target proteins
taxane
anticancer drug
protein-protein disruptor
candidate targets goes after
transmembrane
cytoskeleton
nuclear receptors
what type of drugs attack candidate targets?
anti cancer
anti infectives
microfluidics
combinatory chemistry
comes up with new chemicals
where are compounds discovered?
microfluidics
natural products
bog
due to therapeutics, life expectancy has
increased up 60%
drugs account for ________ of the 60% of increased life expectancy
40%
challenges for drug discovery today?
higher costs
longer timeframes
declining productivity
generics and biosimilars
increased competition
are clinical trials involved in the discovery process?
NO
they are involved in clinical development
how long does it take to get 1 drug approved?
10-20 years
how many drugs are screened in the time one gets approved?
over 10,000
pharmaceuticals and medicines account for _______ of Pharma investments in R&D
12%
are drugs costly?
NO!
only 10 cents per health care dollar
where is drug discovery performed?
big Pharma
biotech companies
biotech companies are
entrepreneurial
who can found a biotech company?
an individuals or a small group of scientists
how many biotech companies in the US?
300 out of 600 total
biotechnology is responsible for
hundred of diagnostic tests (HIV/pregnancy), DNA fingerprinting, etc
Big Pharma challenges
R&D spending growing faster than sales growth
new product discoveries lagging
need licensing from outside
blockbuster drugs off patent
pharmacogenomics
study of how people respond differently to medications due to their genetic inheritance
pharmacogenomics correlates ______________ to ________________
heritable genetic variation
drug response
85% of the differences in patient responses to a drug are due to
genetic polymorphism
drug responses are affected by
pharmacokinetics
pharmacodynamics
pharmacogenomics
pharmacogenoics reduces
the risk of adverse events
pharmacogenomics transforms a _______________ approach into a _____________________ approach
one size fits all
patient sub population
pharmacogenomics improves _____________ and makes for more efficient, cost effective ________________
patient outcomes
drug development process
two types of genetic mutations
single base mutation (SNPs)
insertion/deletion of one or more nucleotide (Tandem repeat or Insertion/deletion polymorphism)
poor metabolizer phenotype
usual dose cleared slower, leads to more drug in the blood
stronger therapeutic effect
normal metabolizer phenotype
usual dose cleared at the expected rate, normal blood levels
expected therapeutic effect
ultra-rapid metabolizer phenotype
usual dose cleared quicker, less drug in the blood
less therapeutic effect
AI has been helpful in
pharmaceutical design and drug discovery
