title: In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase.
abstract: As part of our ongoing efforts to identify natural products with activity against pathogens causing neglected tropical diseases, we are currently performing an extensive screening of natural product (NP) databases against a multitude of protozoan parasite proteins. Within this project, we screened a database of NPs from a commercial supplier, AnalytiCon Discovery (Potsdam, Germany), against Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH), a glycolytic enzyme whose inhibition deprives the parasite of energy supply. NPs acting as potential inhibitors of the mentioned enzyme were identified using a pharmacophore-based virtual screening and subsequent docking of the identified hits into the active site of interest. In a set of 700 structures chosen for the screening, 13 (1.9%) were predicted to possess significant affinity towards the enzyme and were therefore tested in an in vitro enzyme assay using recombinant TbGAPDH. Nine of these in silico hits (69%) showed significant inhibitory activity at 50 µM, of which two geranylated benzophenone derivatives proved to be particularly active with IC50 values below 10 µM. These compounds also showed moderate in vitro activity against T. brucei rhodesiense and may thus represent interesting starting points for further optimization.
authors.affiliation: Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Correnstraße 48, Münster D-48149, Germany. f_herr01@uni-muenster.de.
authors.forename: Fabian C
authors.initials: FC
authors.lastname: Herrmann
authors.affiliation: Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Correnstraße 48, Münster D-48149, Germany. m_lenz01@uni-muenster.de.
authors.forename: Mairin
authors.initials: M
authors.lastname: Lenz
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, University of Münster, PharmaCampus, Correnstraße 48, Münster D-48149, Germany. joachim.jose@uni-muenster.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.affiliation: Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, Basel CH-4002, Switzerland. Marcel.Kaiser@unibas.ch.|University of Basel, Petersplatz 1, Basel CH-4003, Switzerland. Marcel.Kaiser@unibas.ch.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, Basel CH-4002, Switzerland. Reto.Brun@unibas.ch.|University of Basel, Petersplatz 1, Basel CH-4003, Switzerland. Reto.Brun@unibas.ch.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Correnstraße 48, Münster D-48149, Germany. thomschm@uni-muenster.de.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D003198:Computer Simulation; D062313:Databases, Pharmaceutical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases
keywords: Trypanosoma brucei; glyceraldehyde-3-phosphate dehydrogenase inhibitor; human African trypanosomiasis; in silico screening; in vitro antitrypanosomal activity; natural product