Drug design and discovery Flashcards
What is a drug?
Physiological
- A chemical substance used to prevent or cure disease
- A substance which has a physiological effect when introduced into the body
What are the developments in drug discovery?
Characterize, observe
- We can do chemical synthesis
- Can make almost any compound
- Can modify compounds
- We know the structure of compounds
- Can characterize compounds fully
- Can observe in really precise detail what they do in biology and what biology does to them and how they effect cells.
What does an assay do?
Helps decide what drugs are or arent working.
What are hit compounds?
When the drugs have been narrowed down to the ones that work okay.
What can we get from natural products?
Unusual products that we might not make in the lab
What is the main difference between traditional and modern medicine?
Constituents
- The main difference between traditional medicine and modern medicine is that we now have the tools to test how well treatments actually work.
- We can also now separate all the constituents of any particular extract
What are the benefits of natural products?
Biotech, diverse
- All natural products have some kind of biological activity already
- Could be produced by agricultural or biotechnological methods
- Provides access to unusual/diverse structures
What are the drawbacks of natural products?
total
- Can be difficult to obtain in high yields
- Total synthesis challenging
- Compounds are not optimised so need to be modified
- Could be allergens
What is phenotypic screening?
Hypothesis
Approaches looking only at the final effect of a drug, rather than relying on knowledge/hypotheses of how the drug works
How can you make a molecule fit a particular target?
ES or molecule
- A variation of the molecule that the target binds to in nature (either the enzyme-substrate or the molecule which binds to a receptor)
What is docking?
- Calculate where and how well a molecule binds to the target.
- Often using a large virtual library of compounds which could be synthesised.
What is a binding site map?
Creating a model illustrating what arrangement of intermolecular interactions can be addressed.
What is de novo drug design?
Ask the computer to generate a molecule which could bind in the chosen site
What happens if you create a binding site map?
You end up with something very generic and have to find a way to connect the fragments in a way that is synthetically accessible.
What are the benefits of designed synthetic compounds?
Mechanism
- Synthesis straightforward (comparatively)
- Readily modified at any point to tune properties
- Mechanism of action usually well understood
What are the drawbacks of designed synthetic compounds?
- Limited to molecules which are easily made
- Chirality and larger 3D structures rarer
- Does not work so well on proteins without small molecule binding pockets
What do you do in screening?
Assay
Measure each molecule’s interaction with the molecule using well plate based assays
What do you do in selection?
Affinity
Use some affinity measurement to separate binders from non-binders.
What are oligomers?
Chains but not necessarily peptides
What are the benefits of selection?
- Test millions of molecules at once
- Could uncover unexpected activities
- Exploit molecular biology techniques – phage display of peptides, PCR, sequencing, etc.
- Target any protein with larger molecules
What are the drawbacks of selection?
- Might not find any good hits – even a library of >1 million compounds could be poorly designed
- Limited to libraries which can easily be made
- Larger molecules may have trouble getting through membranes etc.
What is in vitro?
On isolated cells, tissues and proteins
What is in vivo?
Entire organisms
For biological assays, is in vitro or in vivo preferred and why?
In vitro is usually preferred for initial tests because it is cheaper, quicker, less controversial, and can be automated.
What does in vitro test for?
This will test whether the drug engages its target, in what fashion, whether it changes the target’s activity, and whether it kills cells.
What are in vivo tests used for?
- In vivo tests will be performed on a smaller selection of compounds – on mice, and potentially other animals.
- They will uncover information about systemic toxicity, absorption, distribution, metabolism, and excretion (ADME).
What is hit-to-lead?
Hit-to-lead: compounds from the library are short-listed according to:
- Synthetic accessibility
- Specificity
- Toxicity
- Physical properties
What is lead optimisation?
Lead optimisation: the compounds will be optimised for:
- Physicochemical properties (polarity, HBs, molecular weight)
- ADME
- Toxicity
What is phase 1 of clinical trials?
Phase I: Testing safety in a small group of healthy volunteers (10 – 100). Safe dosages will be established, and how the body processes the drug (pharmacokinetics) will be monitored. Unblinded = patients and doctors know what the drug is.
What is phase 2 of clinical trials?
Small-scale test for efficacy. 50 – 500 patients with the disease will be enrolled. Safety and pharmacokinetics will be monitored. Placebos are used as a comparison. Either single-blind (patient unaware if they are in the test or placebo group) or double-blind (both unaware).
What is phase 3 of clinical trials?
Phase III: Large scale test for efficacy, with 500 – 3000 or more patients with the disease over many sites. Stringent comparison to existing treatment. Randomised controlled double-blind trials.
What happens after phase 3 of clinical trials?
If Phase III is successful, the company will apply for approval.
What happens in phase 4 of clinical trials?
Phase IV: Follow-up studies are conducted post-approval to monitor response in the wider population.
