title: New chemotypes as Trypanosoma cruzi triosephosphate isomerase inhibitors: a deeper insight into the mechanism of inhibition.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República , Montevideo , Uruguay .
authors: Guzmán
authors: G
authors: Alvarez
authors: Jennyfer
authors: J
authors: Martínez
authors: Beatriz
authors: B
authors: Aguirre-López
authors: Nallely
authors: N
authors: Cabrera
authors: Leticia
authors: L
authors: Pérez-Díaz
authors: Marietta Tuena
authors: MT
authors: de Gómez-Puyou
authors: Armando
authors: A
authors: Gómez-Puyou
authors: Ruy
authors: R
authors: Pérez-Montfort
authors: Beatriz
authors: B
authors: Garat
authors: Alicia
authors: A
authors: Merlino
authors: Mercedes
authors: M
authors: González
authors: Hugo
authors: H
authors: Cerecetto
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D014355:Chagas Disease / Q000188:drug therapy; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D008954:Models, Biological; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010619:Phenazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D013829:Thiadiazines / Q000737:chemistry / Q000494:pharmacology*; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D010619:Phenazines; D013829:Thiadiazines; D014305:Triose-Phosphate Isomerase