A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme
Abstract
:1. Introduction
2. Results
2.1. Virtual Screening
2.2. Biochemical Screening
2.3. Character of UNG Inhibition
2.4. UNG Inhibitors Toxicity Is Independent of Methotrexate
2.5. Inhibition of Vaccinia Virus UNG
3. Discussion
4. Materials and Methods
4.1. Enzymes and Oligonucleotides
4.2. Virtual Screening
4.3. Uracil–DNA Glycosylase Assay
4.4. Inhibition Mechanism Determination
4.5. Cell Toxicity Assay
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Inhibitor | Model | θrela | Vmax, μM/min | KM, μM | Ki, μM |
---|---|---|---|---|---|
3A | competitive | 0.655 | 0.029 ± 0.003 | 1.6 ± 0.5 | 530 ± 270 |
uncompetitive | best model | 0.034 ± 0.004 | 2.6 ± 0.7 | 1300 ± 500 | |
4B | competitive | best model | 0.019 ± 0.001 | 1.1 ± 0.3 | 140 ± 40 |
uncompetitive | 2.53 × 10−5 | 0.024 ± 0.003 | 2.9 ± 0.7 | 550 ± 140 | |
4F | competitive | 0.8 | 0.053 ± 0.014 | 3.1 ± 2.2 | 200 ± 130 |
uncompetitive | best model | 0.075 ± 0.028 | 6.4 ± 4.5 | 250 ± 140 | |
4G | competitive | best model | 0.042 ± 0.002 | 3.7 ± 0.6 | 3300 ± 2300 |
uncompetitive | 0.312 | 0.043 ± 0.003 | 4.2 ± 0.7 | >10,000 |
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Grin, I.R.; Mechetin, G.V.; Kasymov, R.D.; Diatlova, E.A.; Yudkina, A.V.; Shchelkunov, S.N.; Gileva, I.P.; Denisova, A.A.; Stepanov, G.A.; Chilov, G.G.; et al. A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme. Molecules 2021, 26, 6668. https://doi.org/10.3390/molecules26216668
Grin IR, Mechetin GV, Kasymov RD, Diatlova EA, Yudkina AV, Shchelkunov SN, Gileva IP, Denisova AA, Stepanov GA, Chilov GG, et al. A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme. Molecules. 2021; 26(21):6668. https://doi.org/10.3390/molecules26216668
Chicago/Turabian StyleGrin, Inga R., 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, and et al. 2021. "A New Class of Uracil–DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme" Molecules 26, no. 21: 6668. https://doi.org/10.3390/molecules26216668