Computational and Experimental Druggability Assessment of Human DNA Glycosylases.
ACS Omega
; 4(7): 11642-11656, 2019 Jul 31.
Article
in En
| MEDLINE
| ID: mdl-31460271
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.
Full text:
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Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
ACS Omega
Year:
2019
Document type:
Article
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