Zhang, R, McIntyre, PJ, Collins, PM et al. (6 more authors) (2019) Construction of a Shape‐Diverse Fragment Set: Design, Synthesis and Screen against Aurora‐A Kinase. Chemistry - A European Journal, 25 (27). pp. 6831-6839. ISSN 0947-6539
Abstract
Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape‐diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3‐rich molecular scaffolds. The resulting set of 80 fragments was highly three‐dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high‐throughput protein crystallography against Aurora‐A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape‐diverse screening collections to be more fully assessed.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article: Zhang, R, McIntyre, PJ, Collins, PM et al. (6 more authors) (2019) Construction of a Shape‐Diverse Fragment Set: Design, Synthesis and Screen against Aurora‐A Kinase. Chemistry - A European Journal, 25 (27). pp. 6831-6839. ISSN 0947-6539, which has been published in final form at https://doi.org/10.1002/chem.201900815. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
Keywords: | diversity-oriented synthesis; fragments; molecular shape |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Apr 2019 11:33 |
Last Modified: | 26 Apr 2020 00:38 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/chem.201900815 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:144401 |