A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme

A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme Full article

Journal

Molecules
ISSN: 1420-3049

Output data

Year: 2021, Volume: 26, Number: 21, Article number : 6668, Pages count : DOI: 10.3390/molecules26216668

Tags

DNA repair; uracil-DNA glycosylase; inhibitors; virtual screening; pyrimidines

Authors

Grin Inga R. ^1,2 , Mechetin Grigory ¹ , Kasymov Rustem D. ^1,2 , Diatlova Evgeniia A. ¹ , Yudkina Anna ¹ , Shchelkunov Sergei N. ^2,3 , Gileva Irina P. ³ , Denisova Alexandra A. ⁴ , Stepanov Grigoriy A. ⁵ , Chilov Ghermes G. ⁶ , Zharkov Dmitry O. ^1,2

Affiliations

1	(Данные Web of science) SB RAS Inst Chem Biol & Fundamental Med, 8 Lavrentieva Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Novosibirsk State Univ, Dept Nat Sci, 2 Pirogova St, Novosibirsk 630090, Russia
3	(Данные Web of science) State Res Ctr Virol & Biotechnol VECTOR, Koltsov 630559, Novosibirsk Reg, Russia
4	(Данные Web of science) Lomonosov Moscow State Univ, Fac Bioengn & Bioinformat, 1 Leninskie Gory, Moscow 119991, Russia
5	(Данные Web of science) Natl Res Univ, Higher Sch Econ, 20 Myasnitskaya St, Moscow 101000, Russia
6	(Данные Web of science) Russian Acad Sci, Zelinsky Inst Organ Chem, 47 Leninsky Ave, Moscow 119334, Russia

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 & GE; 100 mu M, 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.

Grin I.R. , Mechetin G. , Kasymov R.D. , Diatlova E.A. , Yudkina A. , Shchelkunov S.N. , Gileva I.P. , Denisova A.A. , Stepanov G.A. , Chilov G.G. , Zharkov D.O.
A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
Molecules. 2021. V.26. N21. 6668 . DOI: 10.3390/molecules26216668 WOS Scopus РИНЦ OpenAlex

Published print:

Nov 3, 2021

Web of science:	WOS:000719412500001
Scopus:	2-s2.0-85119618403
Elibrary:	47533342
OpenAlex:	W3208421763

DB	Citing
Web of science	11
Elibrary	10
Scopus	9
OpenAlex	12