Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591089 | Bioorganic & Medicinal Chemistry Letters | 2014 | 16 Pages |
Abstract
Modulation of the vitamin D receptor (VDR) with a ligand has the potential to be useful for the oral treatment of osteoporosis. One component of our lead generation strategy to identify synthetic ligands for VDR included a fragment based drug design approach. Screening of ligands in a VDR fluorescence polarization assay and a RXR/VDR conformation sensing assay resulted in the identification of multiple fragment hits (lean >0.30). These fragment scaffolds were subsequently evaluated for interaction with the VDR ligand binding domain using hydrogen-deuterium exchange (HDX) mass spectrometry. Significant protection of H/D exchange was observed for some fragments in helixes 3, 7, and 8 of the ligand binding domain, regions which are similar to those seen for the natural hormone VD3. The fragments appear to mimic the A-ring of VD3 thereby providing viable starting points for synthetic expansion.
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Authors
Matthew W. Carson, Jun Zhang, Michael J. Chalmers, Wayne P. Bocchinfuso, Karol D. Holifield, Thierry Masquelin, Ryan E. Stites, Keith R. Stayrook, Patrick R. Griffin, Jeffery A. Dodge,