Michel M, Visnes T, Homan EJ, Seashore-Ludlow B, Hedenström M, Wiita E, Vallin K, Paulin CBJ, Zhang J, Wallner O, Scobie M, Schmidt A, Jenmalm-Jensen A, Warpman Berglund U, Helleday T
ACS Omega 4 (7) 11642-11656 [2019-07-31; online 2019-07-05]
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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