Homology modeling and virtual screening approaches to identify potent inhibitors of slingshot phosphatase 1

Although slingshot phosphatase 1 (SSH1) proved to be a promising target for the development of therapeutics for the treatment of vascular diseases and cancers, no small-molecule inhibitor has been reported so far. We have been able to identify eight novel inhibitors of SSH1 through the computer-aided drug design protocol involving homology modeling of SSH1 structure, virtual screening of a large chemical library with docking simulations, and in vitro enzyme assays. The identified inhibitors revealed high potencies with the associated IC50 values ranging from 2.8 to 12.7 μM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure–activity relationship studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the inhibitors in the active site of SSH1 are discussed in detail.

We have identified eight novel inhibitors of SSH1 phosphatase based on the virtual screening with the homology-modeled protein structure.Figure optionsDownload high-quality image (126 K)Download as PowerPoint slideHighlights
► We performed the virtual screening of SSH1 phosphatase inhibitors with docking simulations using the homology-modeled protein structure.
► Eight new inhibitors of SSH1 phosphatase were identified with IC50 values ranging from 2.8 to 12.7 μM.
► Potent inhibitors were found to be capable of simultaneously establishing the strong multiple hydrogen bonds and hydrophobic interactions in the active site.