Cdc25 phosphatases act on cell cycle checkpoints. Several kinds of tumors overexpress this enzyme.Therefore, the study of Cdc25s inhibitors can aid the development of new anticancer therapies. Several low specificity inhibitors have been already described for Cdc25B, isoform which crystal structure of the catalytic domain has been determined by X-ray diffraction. Computational data indicate high flexibilityin the C-terminus that can influence competitive inhibitor binding. In this project, we aim to evaluate and extend these simulations using structural and dynamical measures of the protein in solution obtained by nuclear magnetic resonance. This data will be used to construct new conformational ensembles. The ensembles will be used in docking experiments with inhibitors and the results compared with experimental datafrom the same Cdc25B+inhibitor complexes. Thus, the influence of the protein flexibility in the molecular recognition will be evaluated. This project can lead to important advances in methods used for development of new ligands to flexible or partially unfolded protein.
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