Past Exam Questions Mod 1 Flashcards
Why are natural products important as drug leads, and what are the challenges in developing this source of molecules as drugs?
- important because they have high chemical diversity, biological relevance and historical success
challenges:
- limited supply of natural products
- it can be complex to isolate and synthesise
- complex structures pose lots of difficulties for structural modifications
- low yields
Why is it easier to develop an antagonist or an inhibitor as a drug rather than an agonist?
because its easier to inhibit a molecules which can occur via changing the conformation of the receptor (can be by binding to active or alternative site) rather than finding an identical fit to the active site receptor.
Describe the concept of bioassay-guided fractionation
….?
Name 2 techniques that can be used to help determine the chemical structure of a natural product
- NMR (nuclear magnetic resonance)
- X-ray crystallography
What is the broad definition of HTS and what is the main goal of it?
definition:
the process by which large numbers of compounds can be tested, in an automated fashion, for activity as inhibitors or activators of a particular biological target
main goal: identify a molecular structure (=hit) that
- selectively binds to and modulates the activity of a biological target of interest (target-based)
OR
- selectively induces a desired phenotype in a cell population or organism of interest (phenotype based)
Name 6 terms that are important for HTS and define them
- library - set of compounds to be screened
- target = protein/pathway for drug activity
- lead = precursor of a drug
- hit = compound with a signal above threshold
- false negative = not active against target but scores in assay
- false positive = active against target but fails to score in assay
what is a validated drug target?
a biological molecule (e.g. protein, rna) that has proven to play a critical role in a disease process + whose modulation has demonstration therapeutic potential
What is a therapeutic window and why is it ideal for it to be large?
a therapeutic window is the range of doses of a drug that produces a therapeutic effect without causing significant toxic effects
it is ideal for it to be bigger because:
- it has a greater safety margin when testing or administering in patients
- there is more room for adjusting doses in order to find the most ideal therapeutic effects without causing toxicity
Structure based drug design requires three dimensional atomic resolution structures of receptors and or ligands.
a) What three techniques are capable of providing such structures?
b) Name two advantages of each of these techniques
- X-ray Crystallography
Advantages:
- Very high resolution and accuracy.
- Fast to generate data for different ligands.
Disadvantages:
Requires crystals. Packing artifacts. Not ideal for dynamics. - NMR spectroscopy
Advantages:
- In solution – as in real life!
- Good for dynamic systems.
Disadvantages:
- Lower resolution, can be time consuming.
- Limited to smaller proteins. - Cyro-EM
Ads:
- Easier sample prep and low
amounts
- Excellent for big proteins and
complexes
A chemist in a large pharmaceutical company wants to set up a high-throughput screen to screen a
library of small organic molecules as agonists of a cell-surface receptor.
a) List THREE (3) properties of the library that the chemist should consider in designing the
library for the high-throughput screen. Briefly explain WHY EACH of these properties should
be considered.
- size
- the more compounds in the library, the higher the chance of finding a biologically active compound - cost
- selecting cost-effective compounds can help maximise the number of compounds that can be screened within the budget - diversity
- increased diversity increases the chance of identifying structurally + functionally varied hits = broader range of potential agonists for the target receptor
suggest two possible reasons for false negatives
- assay interference
- non-specific binding
