Generation and Evaluation of a Homology Model ofPfGSK‐3

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-3 beta which are deposited in the protein data base and are crystallized with different ligands. We used ten different HsGSK-3 beta 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.