Research output: Contribution to journal › Article › peer-review
A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme. / Grin, Inga R.; Mechetin, Grigory; Kasymov, Rustem D. et al.
In: Molecules, Vol. 26, No. 21, 6668, 01.11.2021.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
AU - Grin, Inga R.
AU - Mechetin, Grigory
AU - Kasymov, Rustem D.
AU - Diatlova, Evgeniia A.
AU - Yudkina, Anna
AU - Shchelkunov, Sergei N.
AU - Gileva, Irina P.
AU - Denisova, Alexandra A.
AU - Stepanov, Grigoriy A.
AU - Chilov, Ghermes G.
AU - Zharkov, Dmitry O.
N1 - Funding Information: Funding: This research was supported by the Russian Science Foundation (grant No. 17-14-01190 to I.R.G., biochemical and cell work). G.A.S. was funded within the framework of the Academic Fund Program at the HSE University in 2021 (grant No. 21-04-011). Partial salary support from the Russian Ministry of Science and Higher Education (State funded budget projects 0245-2021-0002 and FSUS-2020-0035 to D.O.Z.) is acknowledged. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - DNA repair
KW - uracil-DNA glycosylase
KW - inhibitors
KW - virtual screening
KW - pyrimidines
KW - BASE EXCISION-REPAIR
KW - PROCESSIVITY FACTOR
KW - SELECTIVE-INHIBITION
KW - ESCHERICHIA-COLI
KW - VIRAL-DNA
KW - PROTEIN
KW - UNG
KW - REPLICATION
KW - STRATEGY
KW - SITE
KW - Uracil–DNA glycosylase
KW - Virtual screening
KW - Pyrimidines
KW - Inhibitors
KW - Humans
KW - Vaccinia virus/enzymology
KW - Enzyme Inhibitors/chemistry
KW - Molecular Structure
KW - Pyrimidines/chemistry
KW - Ligands
KW - Molecular Docking Simulation
KW - Kinetics
KW - Uracil-DNA Glycosidase/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85119618403&partnerID=8YFLogxK
U2 - 10.3390/molecules26216668
DO - 10.3390/molecules26216668
M3 - Article
C2 - 34771075
VL - 26
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 21
M1 - 6668
ER -
ID: 34689010