title: Discovery of novel inhibitors of Trypanosoma cruzi trans-sialidase from in silico screening.
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 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK. jneres@hotmail.com
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brewer
authors.forename: Laura
authors.initials: L
authors.lastname: Ratier
authors.forename: Horacio
authors.initials: H
authors.lastname: Botti
authors.forename: Alejandro
authors.initials: A
authors.lastname: Buschiazzo
authors.forename: Philip N
authors.initials: PN
authors.lastname: Edwards
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mortenson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Charlton
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Alzari
authors.forename: Alberto C
authors.initials: AC
authors.lastname: Frasch
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Douglas
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000295:instrumentation / Q000379:methods*; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014349:Trypanosoma cruzi
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; D008024:Ligands; C069715:trans-sialidase; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid