Lecture 1: Drug target identification, validation and high throughput screening Flashcards
Drug phases diagram
Distinguish between the definitions of a drug and medicine? What does the definition of medicine encompass?
Drug: A substance that alters physiological function
Medicine: Legally defined as a substance that is used:
- for the treatment of illness
- for anaesthesia
- for contraception
- for maintaining health
- as a test for diagnosing illness
* The definition of ‘medicine’ encompasses small-molecules, monoclonal antibodies, other therapeutic proteins, vaccines and cells*
Why is a legal definition of medicine required?
Legal definition of a ‘medicine’ is required because marketing authorisation is necessary for them to be sold.
Marketing authorisation is granted by nation states on the advice of regulatory authorities.
Marketing authorisation is a licence to market the medicine in a country. Authorisation can be suspended or revoked (cancelled) if necessary.
Give examples of regulatory authorities?
- UK –Medicines and Healthcare Products Regulatory Agency (MHRA)
- EU –European Medicines Agency (EMEA): handles all biotech products and some specific diseases for all EU
- USA –Food and Drugs Administration (FDA)
Similar bodies exist elsewhere e.g. SFDA in PR China
What is the typical cost of discovery of medicine? What are the chances of success? How many years may it take?
What is the typical cost of discovery of medicine? £1bn
What are the chances of success? | <5%
How many years may it take? | 10-12 years
What are the different origins of new medicines?
- Chemical synthesis of new molecular entities
- Nature
- Rational modification of known drugs or repurposing of existing medicines
- Biotechnology
What is medical chemistry discipline and biotechnology responsible for creating?
Medicinal chemistry à responsible for creating New Molecular Entities (NMEs) – small molecule drugs
Biotechnology à responsible for creating New Biological Entities (NBEs, ‘biologics’). It also engineers’ cells to produce some chemical entities that are synthetically intractable (hard to control) by bench (wet) chemistry
What is biotechnology? Describe its use in the discovery of a small molecule drug?
Biotechnology: involves living system or organism to develop a product
Taxol is a chemotherapy drug used in breast/ovarian/ lung cancer treatment.
It is a natural product found in the bark of the pacific yew tree, but you needed a lot of brak for a little bit of taxol so was not sustainable.
So solution was to take cells from an individual tree and engineer them to produce large amounts of taxol
Describe the traditional route for New Molecular Entities (NMEs)
- Basic research identifies targets (e.g.: receptors, ion channels, that has a role in the disease process)
- Virtual (in silico) and physical chemical libraries are screened for ‘hits’ against target
- Hits are optimised into ‘drug-like’ leads
- Candidate drug
Blue skies research
“research without a clear goal” and “curiosity-driven science”
What are the sources of Targets?
- Industry –Largely focussed research
- Academia –Traditionally ‘blue skies’ research but increasing focus on translatability
- Joint ventures – focussed research often with a ‘blue skies’ component
How many drug targets are there? What does draggability depend on?
Based on human genome there are potentially~30,000 targets
- Of these, 20 –50 % are druggable (receptor agonists and antagonists, ion channel modulators, enzyme inhibitors)
- 50 -80 % are undruggableor ‘difficult’ to access (require modulators of protein-protein interactions)
Druggability depends inter alia (among other things) upon binding site access, site topology, lipophilicity, polarity and H-bond formation
Chemical Libraries*
There are chemical libraries which are a colleciton of chemicals (info about those chemcials are avaible and stored on a database)
You have a target in mind –> you screen this target against those chemicals —-> you get a ‘hit’ = which means there was a chemical that had interactions with that target you were screening for –> this means that this Hit could be a potential drug against that target
What are the different evidences and methods in target ID and Validation?
- Traditional’ ‘ologies’ (physiology, pharmacology, biochemistry etc)
- Systems biology
- Differential gene expression in health and disease
- Differential post-translational modification
- siRNA knock-down; CRISPR-Cas9 gene editing – to identify the involvement of particualr gene prodcuts in porcesses
- Knock-out/knock-in animal models
Describe the start of Chemical Discovery of NMEs
- We could begin on existing structures/precedented chemotypes (to imporve it)
* But this might be protected by patent - Prospecting Compound libraries:
- Physical libraries: used when there is minial data on target.
- Virtual libraries: computational chemistry generally requires high quality structural data for target in order to accelerate hit/lead findin
- Fragment-based screening libraries: approach to find novel structures by using realtively small libaries of small MW compounds. We screen the small libraray agaisnt our target and look for binding of small molecuel – bindig will be weak because they are small fragments (not whole drug). Use this binding info to design a moelcuel that incorporates all binadble fragments (our drug).
Illustrate the challenges of finding a useful compound?
DMPK – Drug metabolism and pharmcokinetic protperties
Desirable, developable molecules exist only at the intersection of several properties of any one CD
