title: Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.
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.
authors.affiliation: Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, Vladimir-Prelog-Weg 3-4, 8093 Zürich (Switzerland).
authors.forename: Daniel
authors.initials: D
authors.lastname: Reker
authors.forename: Michael
authors.initials: M
authors.lastname: Seet
authors.forename: Max
authors.initials: M
authors.lastname: Pillong
authors.forename: Christian P
authors.initials: CP
authors.lastname: Koch
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Witschel
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Céline
authors.initials: C
authors.lastname: Freymond
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Bernd
authors.initials: B
authors.lastname: Schweizer
authors.forename: Boris
authors.initials: B
authors.lastname: Illarionov
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: François
authors.initials: F
authors.lastname: Diederich
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004912:Erythrocytes / Q000469:parasitology; D056945:Hep G2 Cells; D006801:Humans; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry* / Q000633:toxicity; D011758:Pyrroles / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; D011494:Protein Kinases
keywords: computer-assisted drug design; isoprenoid synthase; kinases; medicinal chemistry; target prediction