Computational and Experimental Druggability Assessment
of Human DNA Glycosylases
Version 2 2019-07-05, 11:05Version 2 2019-07-05, 11:05
Version 1 2019-07-04, 08:13Version 1 2019-07-04, 08:13
Posted on 2019-07-05 - 11:05
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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Michel, Maurice; Visnes, Torkild; Homan, Evert J.; Seashore-Ludlow, Brinton; Hedenström, Mattias; Wiita, Elisée; et al. (2019). Computational and Experimental Druggability Assessment
of Human DNA Glycosylases. ACS Publications. Collection. https://doi.org/10.1021/acsomega.9b00162