Virtual Screening Identifies
Novel Sulfonamide Inhibitors
of <i>ecto</i>-5′-Nucleotidase
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Abstract
We aimed to identify inhibitors of <i>ecto</i>-5′-nucleotidase
(<i>ecto</i>-5′-NT, CD73), a membrane-bound metallophosphoesterase
that is implicated in the control of purinergic receptor signaling
and a number of associated therapeutically relevant effects. Currently,
only very few compounds, including ADP, its more stable analogue α,β-methylene-ADP,
ATP, and anthraquinone derivatives are known to inhibit this enzyme.
In the search for inhibitors with more drug-like properties, we applied
a model structure-based virtual screening approach augmented by chemical
similarity searching. On the basis of this analysis, 51 candidate
compounds were finally selected for experimental evaluation. A total
of 13 of these molecules were confirmed to have competitive inhibitory
activity. The most potent inhibitor, 6-chloro-2-oxo-<i>N</i>-(4-sulfamoylphenyl)-2<i>H</i>-chromene-3-carboxylic acid
amide (<b>17</b>), showed an IC<sub>50</sub> value of 1.90 μM.
In contrast to the nucleotide- and anthraquinone-derived antagonists,
the newly identified competitive inhibitors are uncharged at physiological
pH values, possess a drug-like structure, and are structurally distinct
from known active compounds