title: HDX reveals unique fragment ligands for the vitamin D receptor.
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.
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: carson_matthew@lilly.com.
authors: Matthew W
authors: MW
authors: Carson
authors: Department of Molecular Therapeutics, United States.
authors: Jun
authors: J
authors: Zhang
authors: Department of Molecular Therapeutics, United States; The Scripps Research Molecular Screening Center (SRMSC), United States.
authors: Michael J
authors: MJ
authors: Chalmers
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors: Wayne P
authors: WP
authors: Bocchinfuso
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors: Karol D
authors: KD
authors: Holifield
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors: Thierry
authors: T
authors: Masquelin
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors: Ryan E
authors: RE
authors: Stites
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors: Keith R
authors: KR
authors: Stayrook
authors: Department of Molecular Therapeutics, United States; The Scripps Research Molecular Screening Center (SRMSC), United States.
authors: Patrick R
authors: PR
authors: Griffin
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors: Jeffery A
authors: JA
authors: Dodge
mesh_terms: D041961:Deuterium Exchange Measurement; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008024:Ligands; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry / Q000494:pharmacology*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009930:Organic Chemicals; D018167:Receptors, Calcitriol
keywords: Fragment based drug design; Hydrogen–deuterium exchange; Vitamin D receptor