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A Direct-to-Biology High-Throughput Chemistry Approach to Reactive Fragment Screening

preprint
submitted on 23.03.2021, 09:51 and posted on 24.03.2021, 06:58 by Ross P. Thomas, Rachel E. Heap, Francesca Zappacosta, Emma K. Grant, Peter Pogany, Stephen Besley, David J. Fallon, Michael M. Hann, David House, Nicholas C. O. Tomkinson, Jacob T. Bush

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.

Funding

Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation

Engineering and Physical Sciences Research Council

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History

Email Address of Submitting Author

ross.x.thomas@gsk.com

Institution

University of Strathclyde/GlaxoSmithKline

Country

United Kingdom

ORCID For Submitting Author

0000-0002-7883-0210

Declaration of Conflict of Interest

There are no conflicts to declare

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