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Jie Zheng; Small-molecule inhibitors of sFRP1. Invest. Ophthalmol. Vis. Sci. 2013;54(15):778.
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© ARVO (1962-2015); The Authors (2016-present)
Wnt signaling pathways play crucial roles during embryonic development and are also very important in adult tissue maintenance. Abnormal activations of Wnt signaling have been implicated in human diseases including eye related diseases such as glaucoma and retinal related diseases. It has been proposed that the Wnt signaling pathway is a target for therapeutic development. In particular, it has been documented that secreted frizzled-related protein-1 (sFRP1), an antagonist of the Wnt signaling pathway, is differentially expressed in glaucomatous human TM cells compared with normal human TM cells. Furthermore, studies in rodent models and perfusion-cultured human anterior segments suggest that Wnt signaling plays a role in regulating IOP, that increased expression of sFRP1 in the TM is associated with elevated IOP and decreased outflow facility. Therefore restoring Wnt signaling in the TM by inhibiting sFRP1 would be an intervention strategy for treating glaucoma.
Increased computational power has provided us an opportunity to examine proteins and to screen proteins as possible ligands in silico. Structure-based virtual ligand screening is based on known 3D structure of the protein and the small molecules to be screened. Computational models of molecules from small-molecule database are docked to the active site of the target protein. We conducted virtual ligand screen to search for the potential inhibitors of sFRP1. However, despite recent development, the current virtual screening methods still yield a relatively high number of false positive. In our studies, solution NMR spectroscopy was used to filter out those false positive results.
The cysteine-rich domain (CRD) of sFRP1 binds to Wnt molecules and is the functional domain of sFRP1. Through structure-based virtual ligand screening and NMR studies, we initially identified the first inhibitor of the CRD domain of sFRP1 from the ChemDiv small-molecule database. Then, by virtually exploring the existing chemical space and by developing of SAR models, together with additional NMR studies, we have obtained additional small-molecule inhibitors, some of the best drug-like inhibitors bind to the CRD domain of sFRP1 at sub micromolar affinity.
Those small-molecule inhibitors of sFRP1 provide us with a novel approach in glaucoma treatment. Presenting the data at ARVO, we hope that we can establish collaboration with investigators in the glaucoma field to test these compounds.
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