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Fragment-based screening by protein crystallography: successes and pitfalls

Journal Article


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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.

Authors


  •   Chilingaryan, Zorik (external author)
  •   Yin, Zhou (external author)
  •   Oakley, Aaron J.

Publication Date


  • 2012

Citation


  • Chilingaryan, Z., Yin, Z. & Oakley, A. J. (2012). Fragment-based screening by protein crystallography: successes and pitfalls. International Journal of Molecular Sciences, 13 (10), 12857-12879.

Scopus Eid


  • 2-s2.0-84867806564

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=7932&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4589

Number Of Pages


  • 22

Start Page


  • 12857

End Page


  • 12879

Volume


  • 13

Issue


  • 10

Place Of Publication


  • http://www.mdpi.com/1422-0067/13/10/12857

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.

Authors


  •   Chilingaryan, Zorik (external author)
  •   Yin, Zhou (external author)
  •   Oakley, Aaron J.

Publication Date


  • 2012

Citation


  • Chilingaryan, Z., Yin, Z. & Oakley, A. J. (2012). Fragment-based screening by protein crystallography: successes and pitfalls. International Journal of Molecular Sciences, 13 (10), 12857-12879.

Scopus Eid


  • 2-s2.0-84867806564

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=7932&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4589

Number Of Pages


  • 22

Start Page


  • 12857

End Page


  • 12879

Volume


  • 13

Issue


  • 10

Place Of Publication


  • http://www.mdpi.com/1422-0067/13/10/12857