A pharmacophore-based virtual screening approach for the discovery of Trypanosoma cruzi GAPDH inhibitors.
BACKGROUND
Chagas disease is a major cause of morbidity and death for millions of people in Latin America. The drugs currently available exhibit poor efficacy and severe side effects. Therefore, there is an urgent need for new, safe and effective drugs against Chagas disease. The vital dependence on glycolysis as energy source makes the glycolytic enzymes of Trypanosoma cruzi, the causative agent of Chagas disease, attractive targets for drug design. In this work, glyceraldehyde-3-phosphate dehydrogenase from T. cruzi (TcGAPDH) was employed as molecular target for the discovery of new inhibitors as hits.


RESULTS
Integrated protein-based pharmacophore and structure-based virtual screening approaches resulted in the identification of three hits from three chemical classes with moderate inhibitory activity against TcGAPDH. The inhibitors showed IC50 values in the high micromolar range.


CONCLUSIONS
The new chemotypes are attractive molecules for future medicinal chemistry efforts aimed at developing new lead compounds for Chagas disease.
Laboratório de Química Medicinal e Computacional, Centro de Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, Av. João Dagnone 1, 100, 13563-120, São Carlos-SP, Brazil.
Fernando V
FV
Maluf
Adriano D
AD
Andricopulo
Glaucius
G
Oliva
Rafael Vc
RV
Guido
D000595:Amino Acid Sequence; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D018360:Crystallography, X-Ray; D015195:Drug Design; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
D014344:Trypanocidal Agents; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases