Structure-based design of a bisphosphonate 5′(3′)-deoxyribonucleotidase inhibitor

Cellular 5′-nucleotidases regulating nucleotide/nucleoside pools are capable of dephosphorylating phosphomonoesters of important nucleoside analogue drugs, thus decreasing their therapeutic efficacy. Based on previously known inhibitor–enzyme complex structures, we developed a promising inhibitor by...

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Bibliographic Details
Published in:MedChemComm 2015-01, Vol.6 (9), p.1635-1638
Main Authors: Pachl, Petr, Šimák, Ondřej, Řezáčová, Pavlína, Fábry, Milan, Buděšínský, Miloš, Rosenberg, Ivan, Brynda, Jiří
Format: Article
Language:English
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Summary:Cellular 5′-nucleotidases regulating nucleotide/nucleoside pools are capable of dephosphorylating phosphomonoesters of important nucleoside analogue drugs, thus decreasing their therapeutic efficacy. Based on previously known inhibitor–enzyme complex structures, we developed a promising inhibitor by mimicking the phosphate ion and achieved 50- and 100-fold increases in the inhibitory potency towards cdN and mdN, respectively. Crystal structures of both complexes showed major differences in the inhibitor binding mode towards both enzymes.
ISSN:2040-2503
2040-2511
DOI:10.1039/C5MD00235D