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Deorphaning Pyrrolopyrazines as Potent Multi‐Target Antimalarial Agents
Author(s) -
Reker Daniel,
Seet Michael,
Pillong Max,
Koch Christian P.,
Schneider Petra,
Witschel Matthias C.,
Rottmann Matthias,
Freymond Céline,
Brun Reto,
Schweizer Bernd,
Illarionov Boris,
Bacher Adelbert,
Fischer Markus,
Diederich François,
Schneider Gisbert
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201311162
Subject(s) - plasmodium falciparum , proteome , computational biology , kinase , plasmodium berghei , ligand (biochemistry) , drug discovery , biology , mode of action , enzyme , biochemistry , chemistry , malaria , receptor , immunology
The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC 50 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.