Structure-Based Optimization of Bisphosphonate Nucleoside Inhibitors of Human 5(3)-deoxyribonucleotidases

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00495604" target="_blank" >RIV/61388963:_____/18:00495604 - isvavai.cz</a>
Alternative codes found
RIV/68378050:_____/18:00501869 RIV/60461373:22330/18:43915889
Result on the web
<a href="http://dx.doi.org/10.1002/ejoc.201800515" target="_blank" >http://dx.doi.org/10.1002/ejoc.201800515</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ejoc.201800515" target="_blank" >10.1002/ejoc.201800515</a>

Result language
angličtina
Original language name
Structure-Based Optimization of Bisphosphonate Nucleoside Inhibitors of Human 5(3)-deoxyribonucleotidases
Original language description
Cellular 5-nucleotidases, enzymes regulating nucleotide/nucleoside pools, are capable of dephosphorylating phosphomonoesters of important nucleoside analogue drugs, thus decreasing their therapeutic efficacy. Human cytosolic (cdN) as well as mitochondrial (mdN) variants of this enzyme represent interesting targets for development of inhibitory compounds. In this work, bisphosphonate nucleoside derivatives were designed by using a structure-based approach. A second phosphonate group was attached onto a base moiety and by optimization of the linker an increased inhibitor potency towards mdN and cdN was attained. The best compound exhibited inhibition of both enzymes in a nanomolar range, making it the most potent inhibitor of these enzymes prepared to date. In addition, the compounds showed selectivity towards the cdN variant. A series of crystal structures were solved for several inhibitors in the complex with mdN or cdN that provided a structural basis for understanding the inhibition profile of bisphosphonate compounds.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10401 - Organic chemistry

Project
<a href="/en/project/LO1304" target="_blank" >LO1304: Support of suistainability of the Institute of Molecular and Translational Medicine</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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