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Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening

By Turcano, Lorenzo; Torrente, Esther; Missineo, Antonino; Andreini, Matteo; Gramiccia, Marina; Muccio, Trentina Di; Genovese, Ilaria; Fiorillo, Annarita; Harper, Steven; Bresciani, Alberto; et al
From PLoS Neglected Tropical Diseases (2018), 12(11), e0006969. Language: English, Database: CAPLUS, DOI:10.1371/journal.pntd.0006969

Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against Leishmaniasis. This enzyme is fundamental for parasite survival in the host since it reduces trypanothione, a mol. used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize hydrogen peroxide produced by host macrophages during infection. In order to identify new lead compds. against Leishmania we developed and validated a new luminescence-based high-throughput screening (HTS) assay that allowed us to screen a library of 120,000 compds. We identified a novel chem. class of TR inhibitors, able to kill parasites with an IC50 in the low micromolar range. The X-ray crystal structure of TR in complex with a compd. from this class (compd. 3) allowed the identification of its binding site in a pocket at the entrance of the NADPH binding site. Since the binding site of compd. 3 identified by the X-ray structure is unique, and is not present in human homologs such as glutathione reductase (hGR), it represents a new target for drug discovery efforts.

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