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

doi:10.1016/j.bmcl.2008.12.065

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 3, 1 February 2009, Pages 589-596

https://doi.org/10.1016/j.bmcl.2008.12.065 Get rights and content

Abstract

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.

Graphical abstract

Novel inhibitors of Trypanosoma cruzi trans-sialidase, discovered from in silico screening, are reported.

Section snippets

Acknowledgments

J.N. acknowledges financial support to the Portuguese Foundation for Science and Technology (F.C.T.). The work of A.C.F. was partially supported by an International Research Scholar Grant from the Howard Hughes Medical Institute.

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^†: Present address: Center for Drug Design, University of Minnesota, 516 Delaware St. SE, Minneapolis, MN 55455, USA.

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

Abstract

Graphical abstract

Section snippets

Acknowledgments

Trends Parasitol.

Trends Parasitol.

Drug Discov. Today

Cell

Mol. Biochem. Parasitol.

Structure

J. Mol. Biol.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Adv. Drug Deliv. Rev.

J. Mol. Graph. Model.

Mol. Cell

J. Mol. Biol.

Water Res.

J. Mol. Graph. Model.

Anal. Biochem.