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A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
- Source :
- Molecules, Molecules, Vol 26, Iss 6668, p 6668 (2021), Volume 26, Issue 21
- Publication Year :
- 2021
- Publisher :
- MDPI, 2021.
-
Abstract
- Uracil–DNA glycosylases are enzymes that excise uracil bases appearing in DNA as a result of cytosine deamination or accidental dUMP incorporation from the dUTP pool. The activity of Family 1 uracil–DNA glycosylase (UNG) activity limits the efficiency of antimetabolite drugs and is essential for virulence in some bacterial and viral infections. Thus, UNG is regarded as a promising target for antitumor, antiviral, antibacterial, and antiprotozoal drugs. Most UNG inhibitors presently developed are based on the uracil base linked to various substituents, yet new pharmacophores are wanted to target a wide range of UNGs. We have conducted virtual screening of a 1,027,767-ligand library and biochemically screened the best hits for the inhibitory activity against human and vaccinia virus UNG enzymes. Although even the best inhibitors had IC50 ≥ 100 μM, they were highly enriched in a common fragment, tetrahydro-2,4,6-trioxopyrimidinylidene (PyO3). In silico, PyO3 preferably docked into the enzyme’s active site, and in kinetic experiments, the inhibition was better consistent with the competitive mechanism. The toxicity of two best inhibitors for human cells was independent of the presence of methotrexate, which is consistent with the hypothesis that dUMP in genomic DNA is less toxic for the cell than strand breaks arising from the massive removal of uracil. We conclude that PyO3 may be a novel pharmacophore with the potential for development into UNG-targeting agents.
- Subjects :
- pyrimidines
Deamination
Pharmaceutical Science
DNA repair
Vaccinia virus
Ligands
Article
Analytical Chemistry
chemistry.chemical_compound
QD241-441
Drug Discovery
inhibitors
Humans
uracil–DNA glycosylase
Enzyme Inhibitors
Physical and Theoretical Chemistry
Uracil-DNA Glycosidase
chemistry.chemical_classification
Molecular Structure
Organic Chemistry
Uracil
Base excision repair
virtual screening
Molecular Docking Simulation
Kinetics
Enzyme
chemistry
Biochemistry
Chemistry (miscellaneous)
DNA glycosylase
Uracil-DNA glycosylase
Molecular Medicine
Cytosine
DNA
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 26
- Issue :
- 21
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....d097b622de0f7364c5719d8a0d184eab