The structure-based screening and verification of novel cdc25 phosphatase inhibitors

Abstract

The structure-based screening and verification of novel Cdc25 phosphatase inhibitors

Seong Eon Ryu Department of Bio-Engineering, Hanyang University, Seoul, Korea

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. Structural investigations of Cdc25 phosphatases have lagged behind the mechanistic and pharmacological studies. So far, only two X-ray crystal structures of the catalytic domains of Cdc25A and Cdc25B have been reported in their ligand-free forms.

The lack of structural information about the nature of the interactions between Cdc25 phosphatases and small molecule inhibitors has made it a difficult task to discover a good lead compound for anticancer drugs. Virtual screening has not always been successful because of the inaccuracy in the scoring function that leads to a weak correlation between the enrichment in virtual screening and binding mode prediction. The characteristic feature that discriminates our virtual screening approach from the others lies in the implementation of an accurate solvation model in calculating the binding free energy between Cdc25 phosphatases and putative inhibitors, which would have the effect on hit rate in enzyme assay.

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 Cdc25A 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 10μM, they can be considered for further development by structure-activity relationship studies or de novo design methods.