Computational and Experimental Druggability Assessment of Human DNA Glycosylases
| العنوان: | Computational and Experimental Druggability Assessment of Human DNA Glycosylases |
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| المؤلفون: | Karl S. A. Vallin, Cynthia B.J. Paulin, Olov A. Wallner, Thomas Helleday, Jiaxi Zhang, Brinton Seashore-Ludlow, Maurice Michel, Martin Scobie, Ulrika Warpman Berglund, Evert Homan, Mattias Hedenström, Torkild Visnes, Andreas Schmidt, Elisee Wiita, Annika Jenmalm-Jensen |
| المصدر: | 11642-11656 ACS Omega ACS Omega, Vol 4, Iss 7, Pp 11642-11656 (2019) |
| بيانات النشر: | Umeå universitet, Kemiska institutionen, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Thermal shift assay, Human dna, General Chemical Engineering, Druggability, NEIL1, Computational biology, 010402 general chemistry, 01 natural sciences, Article, lcsh:Chemistry, 03 medical and health sciences, Endonuclease, chemistry.chemical_compound, 030304 developmental biology, 0303 health sciences, biology, Chemistry, Assay, Biochemistry and Molecular Biology, General Chemistry, 0104 chemical sciences, lcsh:QD1-999, DNA glycosylase, biology.protein, DNA, Biokemi och molekylärbiologi |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2470-1343 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a979a2138e18910e81cb3df15c169a00 http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-164548 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a979a2138e18910e81cb3df15c169a00 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 24701343 |
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