Structure-based design of a superagonist ligand for the vitamin D nuclear receptor

Chemistry & Biology
Shinji HouraiDino Moras

Abstract

Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clinical applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently associated with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed a superagonist ligand. In order to optimize the aliphatic side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clinical application.

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Citations

Oct 22, 2013·The Journal of Steroid Biochemistry and Molecular Biology·Yoshiyuki Ono
Jul 4, 2012·Protein Expression and Purification·Jinge ZhuFariba M Assadi-Porter
Mar 15, 2011·The Journal of Steroid Biochemistry and Molecular Biology·Amanda M OusleyBahareh Azizi
Apr 20, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Wanda Sicinska, Mateusz Kurcinski
Mar 30, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Silvina Eduardo-CanosaAntonio Mouriño
Dec 8, 2009·Journal of Molecular Biology·Andrew J AnnaloraC David Stout
Aug 16, 2015·British Journal of Pharmacology·R SchrageK Mohr
Mar 28, 2012·Expert Opinion on Therapeutic Patents·Carsten CarlbergAntonio Mouriño
Jun 18, 2014·Frontiers in Physiology·Ferdinand Molnár
Apr 27, 2019·Archiv der Pharmazie·Diego J ObiolAlejandro C Curino
Sep 3, 2016·Endocrine Reviews·Peter J TebbenRajiv Kumar
Nov 16, 2012·Natural Product Reports·Jorge A R SalvadorM Luisa Sá e Melo
Dec 14, 2011·Chemistry : a European Journal·Ramón FragaAntonio Mouriño
Aug 24, 2020·European Journal of Medicinal Chemistry·Jingxuan ChenJianjun Chen
Jul 9, 2010·Journal of Medicinal Chemistry·Yuta SakamakiKeiko Yamamoto
Apr 29, 2011·Journal of Medicinal Chemistry·Maria A RegueiraMercedes Torneiro
Mar 28, 2019·Journal of Medicinal Chemistry·Miguel A MaestroCarsten Carlberg
Sep 11, 2012·Journal of Medicinal Chemistry·Fabrice CiesielskiNatacha Rochel
May 8, 2018·Journal of Medicinal Chemistry·Pranjal GogoiAntonio Mouriño

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