Fragment-based screening by protein crystallography: Successes and pitfalls

Zorik Chilingaryan, Zhou Yin, Aaron J. Oakley

Research output: Contribution to journalReview articlepeer-review

47 Scopus citations


Fragment-based drug discovery (FBDD) concerns the screening of low-molecular weight compounds against macromolecular targets of clinical relevance. These compounds act as starting points for the development of drugs. FBDD has evolved and grown in popularity over the past 15 years. In this paper, the rationale and technology behind the use of X-ray crystallography in fragment based screening (FBS) will be described, including fragment library design and use of synchrotron radiation and robotics for high-throughput X-ray data collection. Some recent uses of crystallography in FBS will be described in detail, including interrogation of the drug targets β-secretase, phenylethanolamine N-methyltransferase, phosphodiesterase 4A and Hsp90. These examples provide illustrations of projects where crystallography is straightforward or difficult, and where other screening methods can help overcome the limitations of crystallography necessitated by diffraction quality.

Original languageEnglish (US)
Pages (from-to)12857-12879
Number of pages23
JournalInternational journal of molecular sciences
Issue number10
StatePublished - Oct 2012
Externally publishedYes


  • Crystallography
  • Drug design
  • Fragment-based screening
  • Synchrotron radiation
  • X-ray

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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