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

초록

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 mu M 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.

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