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

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.