Lead Generation
- Created by: SamDavies
- Created on: 07-01-19 16:55
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- Lead Generation
- Natural products
- Chemicals produced by bacteria, fungi or plants
- Have very complex structures with many stereocentres - unsuitable to made into drugs yet
- Rational design
- Uses a molecule that is known to be active and improves upon it
- E.g. by improving ligand interactions to its binding site
- Drug should now be able to outcompete natural ligand for binding site
- E.g. by improving ligand interactions to its binding site
- Often the drug molecule resembles the natural substrate
- Uses a molecule that is known to be active and improves upon it
- HTS
- Used when you know very little about the drug you are designing
- Screen a large number of compounds, hoping for the right compound for the desired effect
- Hit rates are very low (~1%); made even lower by eliminating those that cause toxicity for example
- Major challenge is separating hits from false positives
- SP2 rich compounds with no stereocentres are easy to synthesise but this results in a flat drug
- Directed screening
- Used when we have some information about the drug but not a lot
- Select certain molecules from a library of compounds, based on some desired properties
- Fragment screen
- We can design fragments of ideal molecules and form bonds between the two if they fit in the active site
- Bonding will be weak
- Now no need to make large quantities of complex ligands
- Fast following
- Building upon previous literature hits from patents or papers
- High competition between companies to create the optimum drug first
- Leads to similar structures of drugs
- Natural products
- Ligand Lipophilicity Efficiency Index (LLE) normalises the potency in relation to lipophilicity
- LLE = pIC50 - LogD
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