Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Reker, D; Seet, M; Pillong, M; Koch, CP; Schneider, P; Witschel, MC; Rottmann, M; Freymond, C; Brun, R; Schweizer, B; Illarionov, B; Bacher, A; Fischer, M; Diederich, F; Schneider, G
Published Date
- July 2014
Published In
Volume / Issue
- 53 / 27
Start / End Page
- 7079 - 7084
PubMed ID
- 24895172
Electronic International Standard Serial Number (EISSN)
- 1521-3773
International Standard Serial Number (ISSN)
- 1433-7851
Digital Object Identifier (DOI)
- 10.1002/anie.201311162
Language
- eng