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Computational and Experimental Druggability Assessment of Human DNA Glycosylases
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2019 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 4, no 7, p. 11642-11656Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 4, no 7, p. 11642-11656
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-164548DOI: 10.1021/acsomega.9b00162ISI: 000482176800036PubMedID: 31460271OAI: oai:DiVA.org:umu-164548DiVA, id: diva2:1365108
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved

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Hedenström, Mattias
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CiteExportLink to record
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  • apa
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