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 2041-6539 (https://doi.org/10.1039/d1sc03551g)

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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 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.

ORCID iDs

Thomas, Ross P., Heap, Rachel E., Zappacosta, Francesca, Grant, Emma K., Pogány, Peter, Besley, Stephen, Fallon, David J. ORCID logoORCID: https://orcid.org/0000-0003-4310-219X, Hann, Michael M., House, David, Tomkinson, Nicholas C. O. ORCID logoORCID: https://orcid.org/0000-0002-5509-0133 and Bush, Jacob T.;
  • Item type:Article
    ID code:77896
    Dates:
    Date
    Event
    28 September 2021
    Published
    11 August 2021
    Published Online
    5 August 2021
    Accepted
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:23 Sep 2021 15:10
    Last modified:17 Nov 2024 05:59
    URI:https://strathprints.strath.ac.uk/id/eprint/77896
CORE (COnnecting REpositories)