Thomas Lemcke

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Name:
Organization: University of Hamburg , Germany
Department:
Title: (PhD)
Co-reporter:Sebastian Kruggel
Archiv der Pharmazie 2009 Volume 342( Issue 6) pp:327-332
Publication Date(Web):
DOI:10.1002/ardp.200800158

Abstract

Plasmodial GSK-3 is a potential new target for malaria therapy. For a structure-based design project, the three-dimensional information of the designated target is needed. Unfortunately, experimental structure data for plasmodial GSK-3 is not yet available. Homology building can be used to generate such three-dimensional structure data using structure information of a homologous protein. GSK-3 possesses a very flexible ATP-binding site, a fact reflected in the variety of X-ray structures of the human GSK-3β which are deposited in the protein data base and are crystallized with different ligands. We used ten different HsGSK-3β templates for the model building of plasmodial GSK-3 and generated 200 models for each template with different modeling protocols. The quality of the models was evaluated with different tools. The results of these evaluations were used to calculate a rank-by-rank consensus score. The top models of this were used to compile an ensemble of PfGSK-3 models that reflect the flexibility of the ATP-binding site and that will be used for the structure-based design of potential ATP-binding site inhibitors of PfGSK-3.

THIENO[3',2':2,3]AZEPINO[4,5-B]INDOL-5(4H)-ONE, 6,11-DIHYDRO-8-NITRO-
INDOLO[3,2-D][1]BENZAZEPINE-6(5H)-THIONE, 7,12-DIHYDRO-9-NITRO-
Pyrido[2',3':2,3]azepino[4,5-b]indol-6(4H)-one, 7,12-dihydro-9-methyl-
INDOLO[3,2-D][1]BENZAZEPIN-6(5H)-ONE, 7,12-DIHYDRO-2-METHOXY-9-NITRO-
INDOLO[3,2-D][1]BENZAZEPIN-6(5H)-ONE, 7,12-DIHYDRO-3-METHOXY-9-NITRO-
Pyrido[2',3':2,3]azepino[4,5-b]indol-6(4H)-one, 9-chloro-7,12-dihydro-
INDOLO[3,2-D][1]BENZAZEPIN-6(5H)-ONE, 9-AMINO-7,12-DIHYDRO-
6,7-dihydro-5H-Pyrido[2,3-b]azepine-5,8(9H)-dione
Ethyl 5-hydroxy-8-oxo-7,9-dihydropyrido[2,3-b]azepine-6-carboxylate
1H-1-BENZAZEPINE-2,5-DIONE, 3,4-DIHYDRO-8-METHOXY-