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PDBsum entry 3zdi
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Transferase/peptide
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PDB id
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3zdi
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References listed in PDB file
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Key reference
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Title
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3,6-Diamino-4-(2-Halophenyl)-2-Benzoylthieno[2,3-B]pyridine-5-Carbonitriles are selective inhibitors of plasmodium falciparum glycogen synthase kinase-3.
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Authors
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W.Fugel,
A.E.Oberholzer,
B.Gschloessl,
R.Dzikowski,
N.Pressburger,
L.Preu,
L.H.Pearl,
B.Baratte,
M.Ratin,
I.Okun,
C.Doerig,
S.Kruggel,
T.Lemcke,
L.Meijer,
C.Kunick.
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Ref.
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J Med Chem, 2013,
56,
264-275.
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PubMed id
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Abstract
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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 IC(50) values against P. falciparum erythrocyte stage
parasites. These results suggest that inhibitors of PfGSK-3 could be developed
as potential antimalarial drugs.
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