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Related Experiment Videos

Fragment-based lead discovery: leads by design.

Robin A E Carr1, Miles Congreve, Christopher W Murray

  • 1Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. r.carr@astex-technology.com

Drug Discovery Today
|July 19, 2005
PubMed
Summary

Fragment-based lead discovery uses small molecules to identify drug leads. These fragments, though weakly binding, offer high ligand efficiency for developing drug candidates with favorable properties.

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Area of Science:

  • Drug discovery and development
  • Medicinal chemistry
  • Biophysics

Background:

  • Fragment-based lead discovery (FBLD) is an alternative to high-throughput screening (HTS).
  • FBLD utilizes smaller, lower molecular weight compounds (120-250 Da) compared to HTS.
  • Fragment hits exhibit lower initial binding affinity (10 microM-mM).

Purpose of the Study:

  • To introduce and explain the principles of fragment-based lead discovery.
  • To highlight the advantages of FBLD over traditional HTS methods.
  • To emphasize the suitability of fragment hits for drug optimization.

Main Methods:

  • Screening of low molecular weight compounds (fragments).
  • Utilizing sensitive biophysical techniques like protein crystallography and NMR for detection.

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  • Assessing ligand efficiency (binding affinity per heavy atom).

    • Main Results:

    • Fragment hits are simpler, less functionalized compounds.
    • Fragments possess high ligand efficiency.
    • FBLD facilitates optimization into clinical candidates with good drug-like properties.

    Conclusions:

    • Fragment-based lead discovery is a viable and efficient approach for identifying novel drug leads.
    • The high ligand efficiency of fragments makes them ideal starting points for medicinal chemistry optimization.
    • FBLD enables the development of drug candidates with improved drug-like characteristics.