Title |
HDX reveals unique fragment ligands for the vitamin D receptor
|
---|---|
Published in |
Bioorganic & Medicinal Chemistry Letters, May 2014
|
DOI | 10.1016/j.bmcl.2014.05.070 |
Pubmed ID | |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Germany | 1 | 3% |
Unknown | 35 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 10 | 28% |
Researcher | 8 | 22% |
Student > Postgraduate | 3 | 8% |
Student > Bachelor | 2 | 6% |
Student > Master | 2 | 6% |
Other | 3 | 8% |
Unknown | 8 | 22% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 10 | 28% |
Chemistry | 9 | 25% |
Biochemistry, Genetics and Molecular Biology | 6 | 17% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
Unknown | 10 | 28% |