PHAR 300 Lecture 6: 6 PHAR300 - Drug design 1
7 Jun 2018
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PHAR300
Drug design 1 : basic research
Evidence based medicine
-whole purpose of developing new drugs is evidence based medicine : without the evidence we
are lost
-it is crucial where we get the evidence
-what kind of evidence do we need : does it work, is it better than a placebo ; if it works, what are
the side effects (ALWAYS SIDE EFFECTS), and who is at risk ; how does it compare to what
is available (if it works a little bit and has less side effects BUT we have a far better drug already
available -> is it worth it to promote something else ? -> no, unfair and unethical to promote
something that works less)
-evidence must be in favor of the drug (benefits are better than the side effects) -> fundamental
concept for all drugs that should be in use
The future
-if we look at the situation we are facing -> causes of death in North America now compared to
1900 -> less deaths due to infectious diseases (pneumonia, influenza, tuberculosis,
gastrointestinal infections…), and more due to cancer and heart diseases
-in the future we hope to see : more personalised therapy (incredible genetic variation between
people => detect which subtype the patient is and select the drug specific to the person to
personalise the treatment)
-drugs that include antibodies, cytokines and specific types of cells (not only chemicals)
-we are already having new types of treatment for cancer
Drug discovery
-stage in the lab where we look for the drug, all the way to the patient => sequence of steps
•Research
-on disease and on potential drugs that could prevent or treat disease
-where the research is done is in the big pharmaceutical drug firms -> spend a lot of money on
research (drug companies are the ones that spend most of their money on research)
-to develop a new drug, it takes :
-time : ~14 years, about 10 years from testing to patient
-money : up to 1.5 billion $US per year
-human resources : 150 researchers in the early stage of basic research
-drug discovery : start with about 10 000 chemical structures that are screened ; and then
reduce the amount in pre-clinical stages -> test the handful and then the remaining chemicals in
clinical trials to finally come up with one that is reviewed by the FDA and then sent to the clinic
-6.5 years from drug discovery to pre-clinical trial
-6 years for clinical trials
-1.5 years FDA review
-if we are lucky, one will pass all the testings and the government approval
-total cost : over 50 billion $ a year
-has worked in many circumstances -> improvement in treatment of some types of cancer
(understood more the biology of cancer, companies started to test compounds that would destroy
the tumor…) => survival rate for many of these is way over 50% -> ways of dealing with cancer
cells improve a lot
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-productivity of the pharma industry -> number of new drugs that reach the market has not been
rising but the amount of money has => harder to develop a drug that we can prove is better
and more effective
-easy ones have already been discovered !
-we have to come up with something better than what already exists
-we don’t understand the fundamental biological abnormalities of some diseases -> more
challenging now than it used to be => costs more money
-e.g. billions of dollars involved in Alzheimer disease research, 16 years of effort, 123 ineffective
drugs
-intraday performance of Eli Lilly’s share price Nov. 23, 2016 -> over $1 billion spent on
new drug for Alzheimer disease tested in humans -> not better than placebo => share price
dropped
-companies need to have the money
and the reserves to cope with this
-e.g. hepatitis C virus -> we finally
have a cure, even though they had to
try various strategies before they got
one
-rejection of drug candidate : lack of
efficacy is the biggest, and then
presence of adverse effects in
people
-developing new antibiotics -> drops
in a straight line -> has to be a lot of
encouragement because of our
antibiotic resistance
Newer drugs
-many of them deal with cancer and autoimmune problems (rhematoid arthritis) -> monoclonal
antibodies MAb -> are made to target a specific receptor on our tumor cell or a specific property
in our immune system that will calm down the autoimmune reaction
-can be very effective
-major changes taking place in various autoimmune diseases, hepatitis C, cancers
•Drug discovery
-labs are the places where the new ideas
come up -> we have to have an idea
-pre-clinical research to show that
there is good evidence that it works
and that there is enough evidence that
it is not going to be harmful
-never gets to human testing unless
strong evidence that it is safe and
effective in the lab
-major challenges in health care that
require basic research
-chronic diseases we need to cure
and prevent : Parkinson’s,
Alzheimers, arthritis
-common killers we need to
prevent / cure : cancer,
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cardiovascular (MI and strokes)
-global concerns : emerging infections (we should plan ahead of time) and pollution and
climate change
-basic research : done in universities / lab funded by government
-drug development : pharmaceutical companies -> translate basic knowledge into something
useful
-we need the idea, the concept : pathogenesis is the crucial thing, understanding the pathology of
the disease
Modelling disease
-overexpression systems, knockouts, small molecule inhibitors, monoclonal antibodies, antisense
oligonucleoties, interference RNA
-we can do that in animals or cells
-drugs can be studied on individual cells, understanding the pathogenesis allows us to develop
effective drugs
-we can use them as models to test different types of drugs
•Identify drug target
-discover what is wrong in a specific disease
-solution would be to : block receptor / stimulate enzyme / add something that is missing… =>
come up with a target
-design drug that can do it
-current drug targets : enzymes, receptors and then ion channels…
-e.g. HIV : protease in the virus with an active site -> this is the target, compare it to human cells
and see if we can interfere with its function
Genomics
-genomics : we now have the human genome
worked out -> we are slowly progressing !
-gene therapy : we have a vector and we can
carry new genes into the cell
-e.g. cystic fibrosis : genetic disorder with a
mutant receptor -> problem with the
airways -> very thick mucus in the airways,
horrific infections
-new receptor can be delivered by nasal
spray into the nose, taken up into the
airway epithelial cells and makes a
functional chloride channel => tremendous
difference
-allows us to profile individual patient : know
individual variations between people
-pregenomics : disease description, uniform
disease, patient homogeneity, universal
therapeutic strategy
-genomics : disease mechanism, disease
heterogeneity, individual variation, patient
risk profiling, pharmacogenomics and targeted care
-also allows us to understand the pathogenesis
-measure gene expression for example in the tumor vs in normal cells => tells us what is wrong
in the tumor
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Document Summary
Whole purpose of developing new drugs is evidence based medicine : without the evidence we are lost. It is crucial where we get the evidence. > no, unfair and unethical to promote something that works less) Evidence must be in favor of the drug (bene ts are better than the side effects) -> fundamental concept for all drugs that should be in use. If we look at the situation we are facing -> causes of death in north america now compared to. 1900 -> less deaths due to infectious diseases (pneumonia, in uenza, tuberculosis, gastrointestinal infections ), and more due to cancer and heart diseases. In the future we hope to see : more personalised therapy (incredible genetic variation between people => detect which subtype the patient is and select the drug speci c to the person to personalise the treatment) Drugs that include antibodies, cytokines and speci c types of cells (not only chemicals)
