title: Discovery of inhibitors of Schistosoma mansoni HDAC8 by combining homology modeling, virtual screening, and in vitro validation.
abstract: Schistosomiasis, caused by S. mansoni, is a tropical disease that affects over 200 million people worldwide. A novel approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during their life cycle. We recently identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here we present results from a virtual screening campaign on smHDAC8. Besides hydroxamates, several sulfonamide-thiazole derivatives were identified by a target-based virtual screening using a homology model of smHDAC8. In vitro testing of 75 compounds identified 8 hydroxamates as potent and lead-like inhibitors of the parasitic HDAC8. Solving of the crystal structure of smHDAC8 with two of the virtual screening hits confirmed the predicted binding mode.
authors.affiliation: Department of Pharmaceutical Chemistry, University Halle-Wittenberg , 06120 Halle/Saale, Germany.
authors.forename: Srinivasaraghavan
authors.initials: S
authors.lastname: Kannan
authors.forename: Jelena
authors.initials: J
authors.lastname: Melesina
authors.forename: Alexander-Thomas
authors.initials: AT
authors.lastname: Hauser
authors.forename: Alokta
authors.initials: A
authors.lastname: Chakrabarti
authors.forename: Tino
authors.initials: T
authors.lastname: Heimburg
authors.forename: Karin
authors.initials: K
authors.lastname: Schmidtkunz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Walter
authors.forename: Martin
authors.initials: M
authors.lastname: Marek
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.forename: Christophe
authors.initials: C
authors.lastname: Romier
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D012550:Schistosoma mansoni / Q000737:chemistry* / Q000201:enzymology; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry*; D014584:User-Computer Interface
chemical_list: D015801:Helminth Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008024:Ligands; D013449:Sulfonamides; D013844:Thiazoles; D006655:Histone Deacetylases