Fragment-Based Drug Discovery and X-Ray Crystallography

Volume 317 of the series Topics in Current Chemistry pp 33-59


Fragment Screening Using X-Ray Crystallography

  • Thomas G. DaviesAffiliated withAstex Therapeutics Ltd Email author 
  • , Ian J. TickleAffiliated withAstex Therapeutics Ltd

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The fragment-based approach is now well established as an important component of modern drug discovery. A key part in establishing its position as a viable technique has been the development of a range of biophysical methodologies with sufficient sensitivity to detect the binding of very weakly binding molecules. X-ray crystallography was one of the first techniques demonstrated to be capable of detecting such weak binding, but historically its potential for screening was under-appreciated and impractical due to its relatively low throughput. In this chapter we discuss the various benefits associated with fragment-screening by X-ray crystallography, and describe the technical developments we have implemented to allow its routine use in drug discovery. We emphasize how this approach has allowed a much greater exploitation of crystallography than has traditionally been the case within the pharmaceutical industry, with the rapid and timely provision of structural information having maximum impact on project direction.


Fragment-based drug discovery Structure-based drug design X-ray crystallography