HDX reveals unique fragment ligands for the vitamin D receptor

被引：22

作者：

Carson, Matthew W. ^{[1
]}

Zhang, Jun

Chalmers, Michael J. ^{[2
]}

Bocchinfuso, Wayne P. ^{[1
]}

Holifield, Karol D. ^{[1
]}

Masquelin, Thierry ^{[1
]}

Stites, Ryan E. ^{[1
]}

Stayrook, Keith R. ^{[1
]}

Griffin, Patrick R. ^{[2
]}

Dodge, Jeffery A. ^{[1
]}

机构：

[1] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Scripps Res Mol Screening Ctr, La Jolla, CA USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 15期

关键词：

Vitamin D receptor; Hydrogen-deuterium exchange; Fragment based drug design; MASS-SPECTROMETRY; EXCHANGE; SELECTIVITY;

D O I：

10.1016/j.bmcl.2014.05.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：3459 / 3463

页数：5

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