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

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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 molecule 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 compounds 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 compounds.We identified a novel chemical class of TR inhibitors, able to kill parasites with an IC 50 in the low micromolar range.The X-ray crystal structure of TR in complex with a compound from this class (compound 3) allowed the identification of its binding site in a pocket at the entrance of the NADPH binding site.Since the binding site of compound 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. Author summaryHuman leishmaniasis is one of the most diffused neglected vector-borne diseases and causes 60,000 deaths annually, a rate surpassed only by malaria among parasitic diseases.Anti-Leishmania treatments are unsatisfactory in terms of their safety and efficacy and there is an urgent need to find treatments.Compounds targeting proteins that are essential for parasite survival but that are not present in the human host are of especial interest with a view to developing selective and non-toxic drugs.Leishmania uses trypanothione as its main detoxifying molecule, allowing the parasite to neutralize the reactive oxygen species produced by macrophages during the infection.Trypanothione is activated by

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