title: Discovery of novel Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase inhibitors.
abstract: Based on its essential role in the life cycle of Trypanosoma cruzi, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been considered a promising target for the development of novel chemotherapeutic agents for the treatment of Chagas' disease. In the course of our research program to discover novel inhibitors of this trypanosomatid enzyme, we have explored a combination of structure and ligand-based virtual screening techniques as a complementary approach to a biochemical screening of natural products using a standard biochemical assay. Seven natural products, including anacardic acids, flavonoid derivatives, and one glucosylxanthone were identified as novel inhibitors of T. cruzi GAPDH. Promiscuous inhibition induced by nonspecific aggregation has been discarded as specific inhibition was not reversed or affected in all cases in the presence of Triton X-100, demonstrating the ability of the assay to find authentic inhibitors of the enzyme. The structural diversity of this series of promising natural products is of special interest in drug design, and should therefore be useful in future medicinal chemistry efforts aimed at the development of new GAPDH inhibitors having increased potency.
authors.affiliation: Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil.
authors.forename: Renato F
authors.initials: RF
authors.lastname: Freitas
authors.forename: Igor M
authors.initials: IM
authors.lastname: Prokopczyk
authors.forename: Aderson
authors.initials: A
authors.lastname: Zottis
authors.forename: Glaucius
authors.initials: G
authors.lastname: Oliva
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Maria Teresa S
authors.initials: MT
authors.lastname: Trevisan
authors.forename: Wagner
authors.initials: W
authors.lastname: Vilegas
authors.forename: Maria Goretti V
authors.initials: MG
authors.lastname: Silva
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Montanari
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D007700:Kinetics; D008958:Models, Molecular; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases