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

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 vir...

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Autores principales:	Inga R. Grin, Grigory V. Mechetin, Rustem D. Kasymov, Evgeniia A. Diatlova, Anna V. Yudkina, Sergei N. Shchelkunov, Irina P. Gileva, Alexandra A. Denisova, Grigoriy A. Stepanov, Ghermes G. Chilov, Dmitry O. Zharkov
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DNA repair uracil–DNA glycosylase inhibitors virtual screening pyrimidines Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/4eccb9b2add64a62a6373d3ddfe88e90
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spelling	oai:doaj.org-article:4eccb9b2add64a62a6373d3ddfe88e902021-11-11T18:37:43ZA New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme10.3390/molecules262166681420-3049https://doaj.org/article/4eccb9b2add64a62a6373d3ddfe88e902021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6668https://doaj.org/toc/1420-3049Uracil–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 IC<sub>50</sub> ≥ 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.Inga R. GrinGrigory V. MechetinRustem D. KasymovEvgeniia A. DiatlovaAnna V. YudkinaSergei N. ShchelkunovIrina P. GilevaAlexandra A. DenisovaGrigoriy A. StepanovGhermes G. ChilovDmitry O. ZharkovMDPI AGarticleDNA repairuracil–DNA glycosylaseinhibitorsvirtual screeningpyrimidinesOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6668, p 6668 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA repair uracil–DNA glycosylase inhibitors virtual screening pyrimidines Organic chemistry QD241-441
spellingShingle	DNA repair uracil–DNA glycosylase inhibitors virtual screening pyrimidines Organic chemistry QD241-441 Inga R. Grin Grigory V. Mechetin Rustem D. Kasymov Evgeniia A. Diatlova Anna V. Yudkina Sergei N. Shchelkunov Irina P. Gileva Alexandra A. Denisova Grigoriy A. Stepanov Ghermes G. Chilov Dmitry O. Zharkov A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
description	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 IC<sub>50</sub> ≥ 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.
format	article
author	Inga R. Grin Grigory V. Mechetin Rustem D. Kasymov Evgeniia A. Diatlova Anna V. Yudkina Sergei N. Shchelkunov Irina P. Gileva Alexandra A. Denisova Grigoriy A. Stepanov Ghermes G. Chilov Dmitry O. Zharkov
author_facet	Inga R. Grin Grigory V. Mechetin Rustem D. Kasymov Evgeniia A. Diatlova Anna V. Yudkina Sergei N. Shchelkunov Irina P. Gileva Alexandra A. Denisova Grigoriy A. Stepanov Ghermes G. Chilov Dmitry O. Zharkov
author_sort	Inga R. Grin
title	A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
title_short	A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
title_full	A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
title_fullStr	A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
title_full_unstemmed	A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
title_sort	new class of uracil–dna glycosylase inhibitors active against human and vaccinia virus enzyme
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4eccb9b2add64a62a6373d3ddfe88e90
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A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme

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