title: Selective inhibitors of Plasmodium falciparum glycogen synthase-3 (PfGSK-3): New antimalarial agents?
abstract: Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) is one of the eukaryotic protein kinases that were identified as essential for the parasite causing malaria tropica. Although the physiological functions of PfGSK-3 are still unknown, it had been suggested as a putative target for novel antimalarial drugs. The high structural similarity of PfGSK-3 and its human orthologue HsGSK-3 makes the development of selective PfGSK-3 inhibitors a challenging task. Actually, established GSK-3 inhibitors are either unselective or are more potent for inhibition of the mammalian GSK-3. A high throughput screening campaign identified thieno[2,3-b]pyridines as a new class of PfGSK-3 inhibitors. Systematic variation of the substitution pattern at the parent scaffold led to compounds which selectively inhibited the plasmodial enzyme. These compounds also exhibited activity against erythrocyte stages of the parasites. A hypothetical explanation for the selectivity of the new antimalarial compounds was enunciated based on the results of docking a selective inhibitor into a PfGSK-3 homology model and by comparison of the results with an X-ray structure of HsGSK-3 co-crystallized with a similar but unselective compound. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
authors: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
authors: Andreas
authors: A
authors: Masch
authors: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany. Electronic address: c.kunick@tu-bs.de.
authors: Conrad
authors: C
authors: Kunick
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity; D011487:Protein Conformation; D058924:Thienopyridines / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D058924:Thienopyridines; D038362:Glycogen Synthase Kinase 3
keywords: Antimalarial; Glycogen synthase kinase-3; Inhibitor; Paullone; Plasmodium; Thieno[2,3-b]pyridine