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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Integration of methods in cheminformatics and biocalorimetry for the design of trypanosomatid enzyme inhibitors

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Autor(es):
Prokopczyk, Igor M. [1] ; Ribeiro, Jean F. R. [1] ; Sartori, Geraldo R. [1] ; Sesti-Costa, Renata [2] ; Silva, Joao S. [2] ; Freitas, Renato F. [1] ; Leitao, Andrei [1] ; Montanari, Carlos A. [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Quim Sao Carlos, Grp Quim Med, BR-13566590 Sao Carlos, SP - Brazil
[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, BR-14049900 Ribeirao Preto, SP - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: Future Medicinal Chemistry; v. 6, n. 1, p. 17-33, JAN 2014.
Citações Web of Science: 7
Resumo

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. Conclusion: 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. (AU)

Processo FAPESP: 11/01893-3 - Otimização de agentes tripanossomatídeos por integração de ensaios in silico, biocalorimétricos e celulares
Beneficiário:Carlos Alberto Montanari
Linha de fomento: Auxílio à Pesquisa - Regular