Discovery of novel inhibitors of Trypanosoma cruzi trans-sialidase from in silico screening |
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Authors: | 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 |
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Affiliation: | 1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK;2. Evotec (UK) Ltd, 114 Milton Park, Abingdon OX14 4SA, UK;3. Instituto de Investigaciones Biotecnologicas, Universidad Nacional de San Martín, CC 30, 1650 San Martín, Argentina;4. Unit of Protein Crystallography, Institut Pasteur de Montevideo, 2020 Mataojo, Montevideo 11400, Uruguay;5. Dept de Biologie Structurale & Chimie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Cedex 15 Paris, France |
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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. |
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