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

Abstract

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 IC50 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.

• Authors: Lorenzo Turcano, Esther Torrente, Antonino Missineo, Matteo Andreini, Marina Gramiccia, Trentina Di Muccio, Ilaria Genovese, Annarita Fiorillo, Steven Harper, Alberto Bresciani, Gianni Colotti, Andrea Ilari
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 12 Issue 11 Pg. e0006969 (11 2018) ISSN: 1935-2735 [Electronic] United States
• PMID: 30475811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Enzyme Inhibitors
• Protozoan Proteins
• NADP
• NADH, NADPH Oxidoreductases
• trypanothione reductase

Topics

• Antiprotozoal Agents (chemistry, metabolism, pharmacology)
• Binding Sites
• Crystallography, X-Ray
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemistry, metabolism, pharmacology)
• High-Throughput Screening Assays
• Humans
• Leishmania (drug effects, enzymology, genetics)
• Leishmaniasis (parasitology)
• Models, Molecular
• NADH, NADPH Oxidoreductases (antagonists & inhibitors, chemistry, genetics, metabolism)
• NADP (metabolism)
• Protozoan Proteins (antagonists & inhibitors, chemistry, genetics, metabolism)