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Molecules 2015, 20(9), 16154-16169; doi:10.3390/molecules200916154

In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase

1
Institut für Pharmazeutische Biologie und Phytochemie (IPBP), University of Münster, PharmaCampus, Correnstraße 48, Münster D-48149, Germany
2
Institut für Pharmazeutische und Medizinische Chemie, University of Münster, PharmaCampus, Correnstraße 48, Münster D-48149, Germany
3
Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, Basel CH-4002, Switzerland
4
University of Basel, Petersplatz 1, Basel CH-4003, Switzerland
Part of a thesis. A preliminary account of this work has been published in abstract form (Planta Med. 2013, 79, 1132).
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 9 July 2015 / Revised: 19 August 2015 / Accepted: 27 August 2015 / Published: 3 September 2015
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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. View Full-Text
Keywords: Trypanosoma brucei; human African trypanosomiasis; glyceraldehyde-3-phosphate dehydrogenase inhibitor; natural product; in silico screening; in vitro antitrypanosomal activity Trypanosoma brucei; human African trypanosomiasis; glyceraldehyde-3-phosphate dehydrogenase inhibitor; natural product; in silico screening; in vitro antitrypanosomal activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Herrmann, F.C.; Lenz, M.; Jose, J.; Kaiser, M.; Brun, R.; Schmidt, T.J. In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase. Molecules 2015, 20, 16154-16169.

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