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Computational and Experimental Druggability Assessment of Human DNA Glycosylases

Computational and Experimental Druggability Assessment of Human DNA Glycosylases

Category
Journal publication
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.
Language
English
Author(s)
  • Michel Maurice
  • Visnes Torkild
  • Homan Evert
  • Seashore-Ludlow Brinton
  • Hedenström Mattias
  • Wiita Elisee
  • Vallin Karl
  • Paulin Cynthia BJ
  • Zhang Jiaxi
  • Wallner Olov
  • Scobie Martin
  • Schmidt Andreas
  • Jenmalm-Jensen Annika
  • Warpman Berglund Ulrika
  • Helleday Thomas
Affiliation
  • Karolinska Institute
  • SINTEF Industry / Biotechnology and Nanomedicine
  • Umeå University
  • Technical University of Clausthal
  • University of Sheffield
Year
2019
Published in
ACS Omega
ISSN
2470-1343
Publisher
American Chemical Society ACS
Volume
4
Issue
7
Page(s)
11642 - 11656