New chemotypes as Trypanosoma cruzi triosephosphate isomerase inhibitors: a deeper insight into the mechanism of inhibition.

Abstract

CONTEXT:

Triosephosphate isomerase (TIM) is a ubiquitous enzyme that has been targeted for the discovery of new small molecular weight compounds used against Trypanosoma cruzi, the causative agent of Chagas disease. We have identified phenazine and 1,2,6-thiadiazine chemotypes as novel inhibitors of TIM from T. cruzi (TcTIM).

OBJECTIVE:

Study the mechanism of TcTIM inhibition by a phenazine derivative and by a 1,2,6-thiadiazine derivative.

METHODS:

We performed biochemical and theoretical molecular docking studies to characterize the interaction of the derivatives with wild-type and mutant TcTIM.

RESULTS AND CONCLUSION:

At low micromolar concentrations, the compounds induce highly selective irreversible inactivation of parasitic TIM. The molecular docking simulations indicate that the phenazine derivative likely interferes with the association of the two monomers of the dimeric enzyme by locating at the dimer interface, while 1,2,6-thiadiazine could act as an inhibitor binding to a region surrounding Cys-118.

• Authors: Guzmán Alvarez, Jennyfer Martínez, Beatriz Aguirre-López, Nallely Cabrera, Leticia Pérez-Díaz, Marietta Tuena de Gómez-Puyou, Armando Gómez-Puyou, Ruy Pérez-Montfort, Beatriz Garat, Alicia Merlino, Mercedes González, Hugo Cerecetto
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 29 Issue 2 Pg. 198-204 (Apr 2014) ISSN: 1475-6374 [Electronic] England
• PMID: 23406473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Enzyme Inhibitors
• Phenazines
• Thiadiazines
• Triose-Phosphate Isomerase

Topics

• Antiprotozoal Agents (chemistry, pharmacology)
• Binding, Competitive
• Chagas Disease (drug therapy)
• Electrophoresis, Polyacrylamide Gel
• Enzyme Inhibitors (chemistry, pharmacology)
• Escherichia coli (genetics)
• Models, Biological
• Molecular Docking Simulation
• Molecular Structure
• Parasitic Sensitivity Tests
• Phenazines (chemistry, pharmacology)
• Protein Binding
• Protein Folding
• Protein Multimerization
• Thiadiazines (chemistry, pharmacology)
• Triose-Phosphate Isomerase (antagonists & inhibitors, chemistry, genetics)
• Trypanosoma cruzi (drug effects, enzymology)