Virtual screening identifies novel sulfonamide inhibitors of ecto-5'-nucleotidase.
We aimed to identify inhibitors of ecto-5'-nucleotidase (ecto-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-N-(4-sulfamoylphenyl)-2H-chromene-3-carboxylic acid amide (17), showed an IC(50) 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.
Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstrasse 2, D-53113 Bonn, Germany.
Peter
P
Ripphausen
Marianne
M
Freundlieb
Andreas
A
Brunschweiger
Herbert
H
Zimmermann
Christa E
CE
Müller
Jürgen
J
Bajorath
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014584:User-Computer Interface
D004791:Enzyme Inhibitors; D013449:Sulfonamides; D015720:5'-Nucleotidase