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Virtual screening identifies novel sulfonamide inhibitors of ecto-5'-nucleotidase.

Abstract

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.

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  • Publisher Full Text
  • Authors

    Ripphausen P, Freundlieb M, Brunschweiger A, Zimmermann H, Müller CE, Bajorath J

    Institution

    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.

    Source

    Journal of medicinal chemistry 55:14 2012 Jul 26 pg 6576-81

    MeSH

    5'-Nucleotidase
    Animals
    Drug Evaluation, Preclinical
    Enzyme Inhibitors
    Inhibitory Concentration 50
    Models, Molecular
    Protein Conformation
    Rats
    Sulfonamides
    User-Computer Interface

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    22731815