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HDX reveals unique fragment ligands for the vitamin D receptor. | LitMetric

HDX reveals unique fragment ligands for the vitamin D receptor.

Bioorg Med Chem Lett

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.

Published: August 2014

AI Article Synopsis

Article 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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2014.05.070DOI Listing

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