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In silico identification and in vitro activity of novel natural inhibitors of
Trypanosoma brucei glyceraldehyde-3-phosphate-dehydrogenase
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID 3247096
Author(s) Herrmann, Fabian C.; Lenz, Mairin; Jose, Joachim; Kaiser, Marcel; Brun, Reto; Schmidt, Thomas J.
Author(s) at UniBasel Kaiser, Marcel; Brun, Reto;
Year 2015
Title In silico identification and in vitro activity of novel natural inhibitors of Trypanosoma brucei
glyceraldehyde-3-phosphate-dehydrogenase
Journal Molecules
Volume 20
Number 9
Pages / Article-Number 16154-16169
Keywords Trypanosoma brucei, human African trypanosomiasis, glyceraldehyde-3-phosphate
dehydrogenase inhibitor, natural product, in silico screening, in vitro antitrypanosomal activity
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.
Publisher MDPI
ISSN/ISBN 1420-3049
edoc-URL http://edoc.unibas.ch/dok/A6438874
Full Text on edoc
No
Digital Object Identifier DOI 10.3390/molecules200916154
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/26404225
ISI-Number WOS:000362505300041
Document type (ISI) Article