期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 3, 页码 589-596出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.12.065
关键词
trans-Sialidase; Inhibitors; Virtual screening; Trypanosoma cruzi; Chagas disease
资金
- Portuguese Foundation for Science and Technology
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. (c) 2008 Elsevier Ltd. All rights reserved.
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