By the same authors

From the same journal

Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures

Research output: Contribution to journalArticlepeer-review


  • Lisa M. Baker
  • Anthony Aimon
  • James B. Murray
  • Allan E. Surgenor
  • Natalia Matassova
  • Stephen D. Roughley
  • Patrick M. Collins
  • Tobias Krojer
  • Frank von Delft
  • Roderick E. Hubbard


Publication details

JournalCommunications Chemistry
DateAccepted/In press - 28 Jul 2020
DateE-pub ahead of print - 2 Sep 2020
DatePublished (current) - 1 Dec 2020
Issue number1
Number of pages11
Early online date2/09/20
Original languageEnglish


Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.

Bibliographical note

© The Author(s) 2020

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