ArticlePloS one2013
Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.Pharmaceuticals (Basel, Switzerland) · 2023Review
- The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones.PloS one · 2023Article
- Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Structure of a cereal purple acid phytase provides new insights to phytate degradation in plants.Plant communications · 2022Article
- Metabolomic Reprogramming of C57BL/6-Macrophages during Early Infection withInternational journal of molecular sciences · 2021Article
- Molecular dynamics free energy simulations of ATP:MgMolecular simulation · 2021Article
- Mechanistic and biological characterisation of novelJournal of enzyme inhibition and medicinal chemistry · 2020Article
- Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.PLoS neglected tropical diseases · 2016Article
- Atomistic insights into the lung cancer-associated L755P mutation in HER2 resistance to lapatinib: a molecular dynamics study.Journal of molecular modeling · 2015Article
- Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach.PLoS neglected tropical diseases · 2015Article
- Stage-dependent expression and up-regulation of trypanothione synthetase in amphotericin B resistant Leishmania donovani.PloS one · 2014Article
- Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modeling.The Journal of biological chemistry · 2013Article
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Authors and funding
7 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two Mg(2+) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows N(1)-glutathionylation of N(8)-glutathionylspermidine, classifying N(8)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N(8)-glutathionylspermidine was characterised as druggable.
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