1 - Drug Discovery Flashcards
Outline the drug discovery process.
Hit finding
Lead discovery
Lead optimisation
Drug development
Through what means can Hit molecules be found?
Me-Too approach
Natural sources
Patent busts
Random screening
Rational target based screening
What are Lipinski’s Rule of Five?
MW < 500 Da
Clogp < 5
H-bond donors < 5
H-bond acceptors < 10
How are natural human agonists often used in drug design?
Natural agonists can be used as leads for antagonists
Natural substrates for enzymes are often used as leads for competitive inhibitors
What’re the advantages of natural drug sources?
Nature has ‘pre-selected’ compounds with pharmacological action - faster than a random search
‘Unusual’ structures not obvious to a chemist can be suggested by nature
What’re the disadvantages of natural drug sources?
Collecting, separating, purifying and characterising compounds can be slow
Natural compounds are often complex, chirality, causing difficulty in synthesis
Natural sources may be hard to access, unreliable and subject to legal issues (bio-piracy)
Whats the issue with ‘conventional synthesis’?
Synthesis in a stepwise manner is slow and time-consuming
- increasing productivity means more people must be employed
Whats the importance of preparing analogues to your lead compound?
To establish SARs —> QSARs
To improve biological profile
To exemplify patents
What’re the benefits of semisynthetic synthesis?
Can be quick
Usually easy to confirm important functional groups in the lead
What’re the disadvantages of semisynthetic synthesis?
Other functional groups in lead may interfere
May not be possible if lead is in short supply - natural source
What is combinatorial synthesis?
Combichem consists of the automated synthesis of small quantities of large numbers of compounds using solid phase methods
What 2 approaches are there to Combichem?
Parallel synthesis
Synthesis of mixtures
What is parallel synthesis?
The same reaction is done on a series of reaction vials, with slightly altered reagents for each vial
Each vial therefore contains only 1 product, whose structure is known on the basis of reagents used
What is the benefit of parallel synthesis? What is it used for?
It allows for the synthesis of large numbers of analogues, and is used for fine-tuning a lead
What is solid phase synthesis?
A resin, often in the form of beads, is used as an inert support for the chemistry being done.
Give an example of a common resin used in solid phase synthesis
What’re the benefits of using molecular modelling?
Cheaper / more powerful computers
Large increase in the structural data of proteins and enzymes from X-ray / NMR
Huge increase in sequence data - e.g. human genome project, 2024 Nobel prize in Chemistry
What is a key idea behind molecular modelling?
Molecular modelling only provides models, not complete answers.
Although it is improving and results are becoming more reliable and accurate
What 2 methods are there to modelling in drug design?
- Structure of target is known
- Structure of a number of inhibitors is known, but target structure is unknown
What methods can be used to determine the structure of proteins/enzymes?
X-ray crystallography
NMR spec
Homology modelling - structure from amino acid sequence (Alphafold2)
What’re the benefits of x-ray crystallography?
Gives complete structure of target - 3D
High resolution
Confirms binding mode
What’re the limitations of x-ray crystallography?
Large quantities of protein, mg, must be crystallised - can be very difficult
Takes several weeks/months to solve structure
Gives structure in ‘solid phase’, whilst most proteins function in solution
Not successful for receptors as they are not crystalline - transmembrane receptors folding also changes outside of membrane domain
What is NMR spectroscopy?
Uses chemical shifts, coupling constants and interatomic interaction to determine structure of protein
Uses Nuclear Overhauser Effect to calculate how close protons are in space
Solves structure in solution - closer to physiological situation
What’re the limitations of NMR spectroscopy?
Only applies to relatively small proteins - up to 200 residues
Takes a long time to solve structure as many NMR experiments must be interpreted
Requires mg quantities of protein - LOTS
