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Computational and Experimental Druggability Assessment of Human DNA Glycosylases

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.
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Category

Academic article

Language

English

Author(s)

  • Maurice Michel
  • Torkild Visnes
  • Evert Homan
  • Brinton Seashore-Ludlow
  • Mattias Hedenström
  • Elisee Wiita
  • Karl Vallin
  • Cynthia BJ Paulin
  • Jiaxi Zhang
  • Olov Wallner
  • Martin Scobie
  • Andreas Schmidt
  • Annika Jenmalm-Jensen
  • Ulrika Warpman Berglund
  • Thomas Helleday

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • Karolinska Institutet
  • Umeå University
  • University of Sheffield
  • Technical University of Clausthal

Year

2019

Published in

ACS Omega

Volume

4

Issue

7

Page(s)

11642 - 11656

View this publication at Norwegian Research Information Repository