Discovery of novel Cdc25 phosphatase inhibitors with micromolar activity based on the structure-based virtual screening

Abstract

Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy because of the correlation of their overexpression with a wide variety of cancers. We have been able to identify five novel Cdc25 phosphatase inhibitors with micromolar activity by means of a computer-aided drug design protocol involving the homology modeling of Cdc25 A and the virtual screening with the automated AutoDock program implementing the effects of ligand solvation in the scoring function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC50 values lower than 10 μM, they can be considered for further development by structure-activity relationship studies or de novo design methods. The differences in binding modes of the identified inhibitors in the active sites of Cdc25A and B are discussed in detail.