3ZDI

Glycogen Synthase Kinase 3 Beta complexed with Axin Peptide and Inhibitor 7d

Summary for 3ZDI

• Entry DOI: 10.2210/pdb3zdi/pdb
• Descriptor: GLYCOGEN SYNTHASE KINASE-3 BETA, AXIN-1, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: transferase-peptide complex, insulin pathway, wnt signaling pathway, transferase serine/threonine-protein kinase, inhibitor, transferase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: P49841 O15169
• Total number of polymer chains: 2
• Total formula weight: 42442.95

Authors

Oberholzer, A.E.,Pearl, L.H. (deposition date: 2012-11-27, release date: 2012-12-26, Last modification date: 2024-10-09)

Primary citation

Fugel, W.,Oberholzer, A.E.,Gschloessl, B.,Dzikowski, R.,Pressburger, N.,Preu, L.,Pearl, L.H.,Baratte, B.,Ratin, M.,Okun, I.,Doerig, C.,Kruggel, S.,Lemcke, T.,Meijer, L.,Kunick, C.
3,6-Diamino-4-(2-Halophenyl)-2-Benzoylthieno(2,3-B) Pyridine-5-Carbonitriles are Selective Inhibitors of Plasmodium Falciparum Glycogen Synthase Kinase-3 (Pfgsk-3)
J.Med.Chem., 56:264-, 2013

PubMed Abstract: Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of PfGSK-3. Taking into account the X-ray structure of a related molecule in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the observed PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC₅₀ values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.

PubMed: 23214499
DOI: 10.1021/JM301575N

Experimental method

X-RAY DIFFRACTION (2.645 Å)