Deorphaning Pyrrolopyrazines as Potent Multi‐Target Antimalarial Agents |
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Authors: | Daniel Reker Dr. Michael Seet Max Pillong Dr. Christian P. Koch Dr. Petra Schneider Dr. Matthias C. Witschel Dr. Matthias Rottmann Céline Freymond Prof. Dr. Reto Brun Dr. Bernd Schweizer Dr. Boris Illarionov Prof. Dr. Adelbert Bacher Prof. Dr. Markus Fischer Prof.Dr. François Diederich Prof. Dr. Gisbert Schneider |
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Affiliation: | 1. Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, Vladimir‐Prelog‐Weg 3‐4, 8093 Zürich (Switzerland);2. inSili.com GmbH, Segantinisteig 3, 8049 Zürich (Switzerland);3. BASF SE, Boschstrasse 14, 67056 Ludwigshafen (Germany);4. Schweizerisches Tropen‐ und Public‐Health Institut, Socinstrasse 57, 4051 Basel (Switzerland);5. Universit?t Basel, Petersplatz 1, 4003 Basel (Switzerland);6. Universit?t Hamburg, Hamburg School of Food Science, Institut für Lebensmittelchemie, Grindelallee 117, 20146 Hamburg (Germany) |
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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. |
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Keywords: | computer‐assisted drug design isoprenoid synthase kinases medicinal chemistry target prediction |
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