title: Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach.
abstract: With the goal to identify novel trypanothione reductase (TR) inhibitors, we performed a combination of in vitro and in silico screening approaches. Starting from a highly diverse compound set of 2,816 compounds, 21 novel TR inhibiting compounds could be identified in the initial in vitro screening campaign against T. cruzi TR. All 21 in vitro hits were used in a subsequent similarity search-based in silico screening on a database containing 200,000 physically available compounds. The similarity search resulted in a data set containing 1,204 potential TR inhibitors, which was subjected to a second in vitro screening campaign leading to 61 additional active compounds. This corresponds to an approximately 10-fold enrichment compared to the initial pure in vitro screening. In total, 82 novel TR inhibitors with activities down to the nM range could be identified proving the validity of our combined in vitro/in silico approach. Moreover, the four most active compounds, showing IC50 values of <1 μM, were selected for determining the inhibitor constant. In first on parasites assays, three compounds inhibited the proliferation of bloodstream T. brucei cell line 449 with EC50 values down to 2 μM.
authors.affiliation: MSD Animal Health Innovation GmbH, Zur Propstei, Schwabenheim, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Beig
authors.affiliation: MSD Animal Health Innovation GmbH, Zur Propstei, Schwabenheim, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Oellien
authors.affiliation: Universität Heidelberg, Biochemie-Zentrum (BZH), Heidelberg, Germany.
authors.forename: Linnéa
authors.initials: L
authors.lastname: Garoff
authors.affiliation: MSD Animal Health Innovation GmbH, Zur Propstei, Schwabenheim, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Noack
authors.affiliation: Universität Heidelberg, Biochemie-Zentrum (BZH), Heidelberg, Germany.
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.affiliation: MSD Animal Health Innovation GmbH, Zur Propstei, Schwabenheim, Germany; Universität Tübingen, Interfakultäres Institut für Biochemie, Tübingen, Germany; Wellcome Trust Centre for Molecular Parasitology, Division of Infection, Immunity and Inflammation, Faculty of Biomedical & Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Selzer
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy*; D002710:Chlorhexidine / Q000494:pharmacology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D011796:Quinacrine / Q000494:pharmacology; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D011796:Quinacrine; D002710:Chlorhexidine; D013095:Spermidine