Computational and Experimental Druggability Assessment of Human DNA Glycosylases

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.