Michel, M., Visnes, T., Homan, E.J. et al. (12 more authors) (2019) Computational and experimental druggability assessment of human DNA glycosylases. ACS Omega, 4 (7). pp. 11642-11656. ISSN 2470-1343
Abstract
Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Apr 2020 13:56 |
Last Modified: | 08 Apr 2020 13:56 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Refereed: | Yes |
Identification Number: | 10.1021/acsomega.9b00162 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:154433 |