Toward the virtual screening of Cdc25A phosphatase inhibitors with the homology modeled protein structure.

Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their overexpression with a wide variety of cancers. As a method for the discovery of novel inhibitors of Cdc25 phosphatases, we have evaluated the computer-aided drug design protocol involving the homology modeling of Cdc25A and virtual screening with the two docking tools: FlexX and the modified AutoDock program implementing the effects of ligand solvation in the scoring function. The homology modeling with the X-ray crystal structure of Cdc25B as a template provides a high-quality structure of Cdc25A that enables the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of Cdc25A through the simultaneous establishment of the multiple hydrogen bonds and the hydrophobic interactions. The present study demonstrates the usefulness of the modified AutoDock program as a docking tool for virtual screening of new Cdc25 phosphatase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors.