期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 6, 期 21, 页码 3935-3947出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/b806371k
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资金
- Novartis
- UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)
- Deutsche Forschungsgemeinschaft [SFB 544]
Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a. flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the mepacrine binding site near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC50 values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.
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