title: Integration of methods in cheminformatics and biocalorimetry for the design of trypanosomatid enzyme inhibitors.
abstract: BACKGROUND
  The enzyme gapdh, which acts in the glycolytic pathway, is seen as a potential target for pharmaceutical intervention of chagas disease.
  
  
  RESULTS
  Herein, we report the discovery of new Trypanosoma cruzi GAPDH (TcGAPDH) inhibitors from target- and ligand-based virtual screening protocols using isothermal titration calorimetry (ITC) and molecular dynamics. Molecular dynamics simulations were used to gain insight on the binding poses of newly identified inhibitors acting at the TcGAPDH substrate (G3P) site.
  
  
  CONCLUSIONS
  Nequimed125, the most potent inhibitor to act upon TcGAPDH so far, which sits on the G3P site without any contact with the co-factor (NAD(+)) site, underpins the result obtained by ITC that it is a G3P-competitive inhibitor. Molecular dynamics simulation provides biding poses of TcGAPDH inhibitors that correlate with mechanisms of inhibition observed by ITC. Overall, a new class of dihydroindole compounds that act upon TcGAPDH through a competitive mechanism of inhibition as proven by ITC measurements also kills T. cruzi.
authors.affiliation: Grupo de Química Medicinal do Instituto de Química de São Carlos da Universidade de São Paulo Av. Trabalhador Sancarlense, 400, 13566-590, São Carlos/SP, Brazil.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Prokopczyk
authors.forename: Jean F R
authors.initials: JF
authors.lastname: Ribeiro
authors.forename: Geraldo R
authors.initials: GR
authors.lastname: Sartori
authors.forename: Renata
authors.initials: R
authors.lastname: Sesti-Costa
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Renato F
authors.initials: RF
authors.lastname: Freitas
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitão
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Montanari
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology; D013816:Thermodynamics; D014344:Trypanocidal Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases