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

• Published in: Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (3), p.589-596
• Main Authors: Neres, João, Brewer, Mark L., Ratier, Laura, Botti, Horacio, Buschiazzo, Alejandro, Edwards, Philip N., Mortenson, Paul N., Charlton, Michael H., Alzari, Pedro M., Frasch, Alberto C., Bryce, Richard A., Douglas, Kenneth T.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Binding Sites; Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; Catalytic Domain; Chagas disease; Chemical Sciences; Chemistry, Pharmaceutical; Chemistry, Pharmaceutical - instrumentation; Chemistry, Pharmaceutical - methods; Cristallography; Crystallization; Crystallography, X-Ray; Crystallography, X-Ray - methods; Drug Design; Enzyme Inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycoproteins; Glycoproteins - antagonists & inhibitors; Glycoproteins - chemistry; Inhibitors; Inhibitory Concentration 50; Kinetics; Life Sciences; Ligands; Medical sciences; Models, Chemical; N-Acetylneuraminic Acid; N-Acetylneuraminic Acid - chemistry; Neuraminidase; Neuraminidase - antagonists & inhibitors; Neuraminidase - chemistry; Pharmacology. Drug treatments; trans-Sialidase; Trypanosoma cruzi; Virtual screening
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.065

Novel inhibitors of Trypanosoma cruzi trans-sialidase, discovered from in silico screening, are reported. 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 IC 50 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.