Discovery of novel inhibitors of Trypanosoma cruzi trans-sialidase from in silico screening

João Neres, Mark L. Brewer, Laura Ratier, Horacio Botti, Alejandro Buschiazzo, Philip N. Edwards, Paul N. Mortenson, Michael H. Charlton, Pedro M. Alzari, Alberto C. Frasch, Richard A. Bryce, Kenneth T. Douglas

    Research output: Contribution to journalArticlepeer-review


    trans-Sialidase from Trypanosoma cruzi (TcTS) has emerged as a potential drug target for treatment of Chagas disease. Here, we report the results of virtual screening for the discovery of novel TcTS inhibitors, which targeted both the sialic acid and sialic acid acceptor sites of this enzyme. A library prepared from the Evotec database of commercially available compounds was screened using the molecular docking program GOLD, following the application of drug-likeness filters. Twenty-three compounds selected from the top-scoring ligands were purchased and assayed using a fluorimetric assay. Novel inhibitor scaffolds, with IC50 values in the submillimolar range were discovered. The 3-benzothiazol-2-yl-4-phenyl-but-3-enoic acid scaffold was studied in more detail, and TcTS inhibition was confirmed by an alternative sialic acid transfer assay. Attempts to obtain crystal structures of these compounds with TcTS proved unsuccessful but provided evidence of ligand binding at the active site. © 2008 Elsevier Ltd. All rights reserved.
    Original languageEnglish
    Pages (from-to)589-596
    Number of pages7
    JournalBioorganic and Medicinal Chemistry Letters
    Issue number3
    Publication statusPublished - 1 Feb 2009


    • Chagas disease
    • Inhibitors
    • trans-Sialidase
    • Trypanosoma cruzi
    • Virtual screening


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