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
    • 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
  • Ligand Lipophilicity Efficiency Index (LLE) normalises the potency in relation to lipophilicity
  • LLE = pIC50 - LogD


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