Fragment-based screening by protein crystallography

Successes and pitfalls

Zorik Chilingaryan, Zhou Yin, Aaron J. Oakley

Research output: Contribution to journalReview article

26 Citations (Scopus)

Abstract

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
Volume13
Issue number10
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

Crystallography
crystallography
Screening
screening
fragments
Drug Discovery
proteins
Proteins
drugs
Phenylethanolamine N-Methyltransferase
Type 4 Cyclic Nucleotide Phosphodiesterase
Macromolecular Substances
Amyloid Precursor Protein Secretases
Synchrotrons
X Ray Crystallography
Robotics
Pharmaceutical Preparations
X ray crystallography
Molecular Weight
Synchrotron radiation

Keywords

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

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Spectroscopy
  • Inorganic Chemistry
  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Medicine(all)

Cite this

Fragment-based screening by protein crystallography : Successes and pitfalls. / Chilingaryan, Zorik; Yin, Zhou; Oakley, Aaron J.

In: International Journal of Molecular Sciences, Vol. 13, No. 10, 2012, p. 12857-12879.

Research output: Contribution to journalReview article

Chilingaryan, Zorik ; Yin, Zhou ; Oakley, Aaron J. / Fragment-based screening by protein crystallography : Successes and pitfalls. In: International Journal of Molecular Sciences. 2012 ; Vol. 13, No. 10. pp. 12857-12879.
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