Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.
Angew Chem Int Ed Engl
; 53(27): 7079-84, 2014 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-24895172
ABSTRACT
The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piridazinas
/
Pirroles
/
Antimaláricos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2014
Tipo del documento:
Article