Structure-based de novo design of Eya2 phosphatase inhibitors

Although Eyes absent protein tyrosine phosphatases proved to be involved in various human cancers by a series of persuasive experimental evidence, only a very few number of small-molecule inhibitors have been reported so far. We have been able to identify 29 novel inhibitors of Eyes absent homologue 2 (Eya2) by means of a structure-based de novo design with the two known inhibitor scaffolds that contain a proper chelating group for the active-site Mg2+ ion. Because these newly found inhibitors were screened for having desirable physicochemical properties as a drug candidate and exhibited a moderate inhibitory activity with IC50 values ranging from 6 to 50 μM, they deserve consideration for further investigation to develop new anticancer medicines. Structural features relevant to the stabilization of the identified inhibitors in the active site of Eya2 phosphatase are discussed in detail.

We have identified 29 novel inhibitors of Eya2 phosphatase based on the structure-based de novo design approach.Figure optionsDownload high-quality image (110 K)Download as PowerPoint slideHighlights
► We performed structure-based de novo designs using the scoring function implementing the solvation free energy of a ligand.
► 29 new inhibitors of Eya2 phosphatase were identified from the two known inhibitor scaffolds.
► Potent inhibitors were found to be capable of simultaneously establishing the coordination to the Mg2+ ion, multiple hydrogen bonds, and hydrophobic interactions in the active site.