A direct-to-biology high-throughput chemistry approach to reactive fragment screening

Ross P. Thomas, Rachel E. Heap, Francesca Zappacosta, Emma K. Grant, Peter Pogány, Stephen Besley, David J. Fallon, Michael M. Hann, David House, Nicholas C. O. Tomkinson, Jacob T. Bush

Research output: Contribution to journalArticlepeer-review

Abstract

Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of new medicines. Here, we report a screening platform that combines ‘direct-to-biology’ high-throughput chemistry (D2B-HTC) with photoreactive fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates in 24 h and their subsequent screening as crude reaction products with a protein target without purification. Screening the HTC-PhABit library with carbonic anhydrase I (CAI) afforded 7 hits (0.7% hit rate), which were found to covalently crosslink in the Zn2+ binding pocket. A powerful advantage of the D2B-HTC screening platform is the ability to rapidly perform iterative design–make–test cycles, accelerating the development and optimisation of chemical tools and medicinal chemistry starting points with little investment of resource.
Original languageEnglish
Pages (from-to)12098-12106
Number of pages9
JournalChemical Science
Volume12
Issue number36
Early online date11 Aug 2021
DOIs
Publication statusPublished - 28 Sep 2021

Keywords

  • medicinal chemistry
  • compound synthesis
  • high-throughput chemistry (HTC)
  • direct-to-biology (D2B) screening
  • D2B-HTC photoreactive fragment screening platform (HTC-PhABits)

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