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Fragment-based lead discovery using X-ray crystallography.

Michael J Hartshorn1, Christopher W Murray, Anne Cleasby

  • 1Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.

Journal of Medicinal Chemistry
|January 22, 2005
PubMed
Summary
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Fragment screening using X-ray crystallography identifies small molecule binders for drug discovery. These fragments, though weakly potent, serve as effective starting points for developing new drug leads.

Area of Science:

  • Structural Biology
  • Drug Discovery
  • Biophysics

Background:

  • Traditional drug screening methods can be time-consuming and costly.
  • Fragment screening offers a promising alternative for identifying novel drug leads.
  • High-throughput X-ray crystallography provides a powerful tool for fragment-based drug discovery.

Purpose of the Study:

  • To describe a fragment screening methodology utilizing high-throughput X-ray crystallography.
  • To demonstrate the application of this method across five different protein targets.
  • To highlight the potential of fragment screening for lead compound identification.

Main Methods:

  • High-throughput X-ray crystallography was employed for fragment screening.
  • The methodology was tested against five diverse protein targets: p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B.

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  • Analysis focused on identifying efficient binders relative to fragment size.

    • Main Results:

    • Weakly potent fragments ( >100 microM) were identified as efficient binders.
    • Fragment binding was driven by various molecular interactions, including lipophilic, charge-charge, and hydrogen bonds.
    • Protein movement induced by fragment binding was observed, indicating conformational flexibility.

    Conclusions:

    • Fragment screening via high-throughput X-ray crystallography is a viable strategy for drug discovery.
    • Identified fragments serve as excellent starting points for lead compound optimization.
    • This approach holds significant potential for discovering novel therapeutics against diverse biological targets.