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

Thomas, Ross P. and Heap, Rachel E. and Zappacosta, Francesca and Grant, Emma K. and Pogány, Peter and Besley, Stephen and Fallon, David J. and Hann, Michael M. and House, David and Tomkinson, Nicholas C. O. and Bush, Jacob T. (2021) A direct-to-biology high-throughput chemistry approach to reactive fragment screening. Chemical Science, 12 (36). pp. 12098-12106. ISSN 2041-6520 (https://doi.org/10.1039/d1sc03551g)

[thumbnail of Thomas-etal-CS-2021-A-direct-to-biology-high-throughput-chemistry-approach-to-reactive-fragment-screening]
Text. Filename: Thomas_etal_CS_2021_A_direct_to_biology_high_throughput_chemistry_approach_to_reactive_fragment_screening.pdf
Final Published Version
License: Creative Commons Attribution 4.0 logo

Download (1MB)| Preview


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.