Planejamento de inibidores das enzimas diidroorotato desidrogenase de Trypanosoma cruzi e Leishmania major / Design of inhibitors for dihydroorotate dehydrogenase from Trypanosoma cruzi and Leishmania major

AUTOR(ES)

Matheus Pinto Pinheiro

FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

25/04/2012

RESUMO

Dihydroorotate dehydrogenase (DHODH) catalyses the conversion of dihydroorote to orotate, the fourth step and only redox reaction in the de novo pyrimidine biosynthetic pathway. DHODH has been exploited as a validated target for therapy against proliferative and parasitic diseases, and in particular, has been considered to be an attractive target for drug development against trypanosomatids, such as parasites from the genera Leishmania and Trypanosoma that collectively cause disease and death in millions of humans. In this work, by combining recombinant DNA technology, thermofluor, X-ray crystallography and in vitro and in silico inhibition assays, we have been able to identify target sites for ligand design, identify potent and selective inhibitors against trypanosomatid DHODHs and fully characterize their mechanism of inibition. Finally, the anti-leishmanial effect observed in our anti-promastigote assays and the low citotoxicity levels observed against mammaliam cells strongly suggest that some of the compounds identified during the development of this project as potent DHODH inhibitors can be used as prototytes for the development of anti-leishmania and anti-trypanosoma drugs. Altogether, our findings provide a new and important contribution to the understanding of the mechanism of action of class 1A DHODHs and for the structure-assisted design of inhibitors against trypanosomatid DHODHs. Furthermore, the high sequence and structural similarity observed among trypanosomatid DHODH suggest that a single strategy of structure-based inhibitor design can be used to exploit DHODH as a druggable target against multiple neglected tropical diseases such as Leishmaniasis, Sleeping Sickness and Chagas\ Disease.

ASSUNTO(S)

dihydroorotate dehydrogenase diidroorotato desidrogenase docagem docking inhibitor design leishmania major leishmania major planejamento de inibidores trypanosoma cruzi cepa y trypanosoma cruzi y strain x-ray crystallography cristalografia de raios-x.

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