Discovery of novel inhibitors of Trypanosoma cruzi trans-sialidase from in silico screening
| Autor: | Alberto C.C. Frasch, Michael H. Charlton, Paul N. Mortenson, Richard A. Bryce, Horacio Botti, Mark L. Brewer, Pedro M. Alzari, Alejandro Buschiazzo, João Neres, Kenneth T. Douglas, Laura Ratier, Philip Neil Edwards |
|---|---|
| Přispěvatelé: | University of Manchester [Manchester], Evotec, Universidad Nacional de San Martin (UNSAM), Protein Crystallography / Cristalografía de Proteínas [Montevideo], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Département de Biologie structurale et Chimie - Department of Structural Biology and Chemistry, Institut Pasteur [Paris], 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., Institut Pasteur [Paris] (IP) |
| Rok vydání: | 2009 |
| Předmět: |
Chemistry
Pharmaceutical Clinical Biochemistry MESH: Catalytic Domain Pharmaceutical Science MESH: Drug Design Crystallography X-Ray Ligands 01 natural sciences Biochemistry chemistry.chemical_compound Catalytic Domain Drug Discovery MESH: Ligands MESH: Animals Enzyme Inhibitors MESH: Crystallization MESH: Inhibitory Concentration 50 chemistry.chemical_classification 0303 health sciences MESH: Kinetics biology MESH: Models Chemical MESH: Neuraminidase 3. Good health MESH: Enzyme Inhibitors Enzyme inhibitor Molecular Medicine MESH: N-Acetylneuraminic Acid Crystallization MESH: Trypanosoma cruzi Trypanosoma cruzi In silico MESH: Glycoproteins Neuraminidase Sialidase Inhibitory Concentration 50 MESH: Chemistry Pharmaceutical 03 medical and health sciences [CHIM.CRIS]Chemical Sciences/Cristallography Animals [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Molecular Biology Glycoproteins 030304 developmental biology Virtual screening Binding Sites 010405 organic chemistry Organic Chemistry Active site MESH: Crystallography X-Ray biology.organism_classification N-Acetylneuraminic Acid 0104 chemical sciences Sialic acid Kinetics Enzyme Models Chemical MESH: Binding Sites chemistry Drug Design biology.protein |
| Zdroj: | Bioorganic and Medicinal Chemistry Letters Bioorganic and Medicinal Chemistry Letters, Elsevier, 2009, 19 (3), pp.589-596. ⟨10.1016/j.bmcl.2008.12.065⟩ Bioorganic and Medicinal Chemistry Letters, 2009, 19 (3), pp.589-596. ⟨10.1016/j.bmcl.2008.12.065⟩ |
| ISSN: | 0960-894X |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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