Issue 36, 2021

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

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
29 Jun 2021
Accepted
05 Aug 2021
First published
11 Aug 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 12098-12106

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

R. P. Thomas, R. E. Heap, F. Zappacosta, E. K. Grant, P. Pogány, S. Besley, D. J. Fallon, M. M. Hann, D. House, N. C. O. Tomkinson and J. T. Bush, Chem. Sci., 2021, 12, 12098 DOI: 10.1039/D1SC03551G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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