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Issue 9, 2015
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Structure-based design of a bisphosphonate 5′(3′)-deoxyribonucleotidase inhibitor

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Abstract

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.

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

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Article information


Submitted
03 Jun 2015
Accepted
20 Jul 2015
First published
23 Jul 2015

Med. Chem. Commun., 2015,6, 1635-1638
Article type
Concise Article

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

P. Pachl, O. Šimák, P. Řezáčová, M. Fábry, M. Buděšínský, I. Rosenberg and J. Brynda, Med. Chem. Commun., 2015, 6, 1635
DOI: 10.1039/C5MD00235D

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