10 research outputs found
The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation.
In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought
Virtual Screening Identifies Novel Sulfonamide Inhibitors of <i>ecto</i>-5′-Nucleotidase
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