Molecular features of thymidine analogues governing the activity of human thymidine kinase

Karolina Jagiełło , Samanta Makurat , Sylwester Pereć , Janusz Rak , Tomasz Puzyn

Abstract

Modified uridines seem to be able to work as hypoxic tumour cell radiosensitisers. Before they sensitise cells to ionising radiation, they have to be incorporated into the genomic DNA and the latter process has to be preceded by the phosphorylation of the modified uridine, which in human cells is executed by human thymidine kinase 1 (hTK1). In the current study, we present the quantitative structure-activity relationship (QSAR) model allowing to identify and understand the molecular features of nucleoside derivatives governing the hTK1 kinase activity. The developed model meets all requirements of a reliable QSAR model and is based on only two molecular properties: the shape of the nucleoside determined by atom substitutions and the ability of the molecule to intermolecular interactions with the enzyme. These results have important implications for the rational designing of new hTK1 substrates and should significantly reduce the time and cost of studies on new radiosensitisers.
Author Karolina Jagiełło (FCh / DEChR / LECh)
Karolina Jagiełło,,
- Laboratory of Environmental Chemometrics
, Samanta Makurat (FCh / DPCh / LBS)
Samanta Makurat,,
- Laboratory of Biological Sensitizers
, Sylwester Pereć (FCh / DEChR / LECh)
Sylwester Pereć,,
- Laboratory of Environmental Chemometrics
, Janusz Rak (FCh / DPCh / LBS)
Janusz Rak,,
- Laboratory of Biological Sensitizers
, Tomasz Puzyn (FCh / DEChR / LECh)
Tomasz Puzyn,,
- Laboratory of Environmental Chemometrics
Journal seriesStructural Chemistry, ISSN 1040-0400, (A 25 pkt)
Issue year2018
Vol29
No5
Pages1367-1374
Publication size in sheets0.5
Keywords in Englishhuman thymidine kinase 1, QSAR model, nucleoside analogues, deoxythymidine, substrate specificity, molecular descriptors
DOIDOI:10.1007/s11224-018-1124-2
URL https://doi.org/10.1007/s11224-018-1124-2
Languageen angielski
Score (nominal)25
ScoreMinisterial score = 25.0, 19-07-2018, ArticleFromJournal
Ministerial score (2013-2016) = 25.0, 19-07-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 1.582 (2) - 2016=1.372 (5)
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