Baker, Lisa M., Aimon, Anthony, Murray, James B. et al. (7 more authors) (2020) Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures. Communications Chemistry. 122. ISSN 2399-3669
Abstract
Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2020 |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 16 Sep 2020 15:10 |
Last Modified: | 01 Dec 2024 01:16 |
Published Version: | https://doi.org/10.1038/s42004-020-00367-0 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s42004-020-00367-0 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:165653 |
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Description: Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures
Licence: CC-BY 2.5