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

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Thomas, Ross P. and Heap, Rachel E. and Zappacosta, Francesca and Grant, Emma K. and Pogany, Peter and Besley, Stephen and Fallon, David J. and Hann, Michael M. and House, David and Tomkinson, Nick C. O. and Bush, Jacob T. (2021) A direct-to-biology high-throughput chemistry approach to reactive fragment screening. Other. ChemRxiv, Cambridge. (https://doi.org/10.26434/chemrxiv.14261780.v1)

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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 covalent fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates. 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.

ORCID iDs

Thomas, Ross P., Heap, Rachel E., Zappacosta, Francesca, Grant, Emma K., Pogany, Peter, Besley, Stephen, Fallon, David J., Hann, Michael M., House, David, Tomkinson, Nick C. O. ORCID logoORCID: https://orcid.org/0000-0002-5509-0133 and Bush, Jacob T.;
CORE (COnnecting REpositories)