Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands

Bioorg Med Chem Lett. 2011 Oct 15;21(20):6104-7. doi: 10.1016/j.bmcl.2011.08.047.

Yosuke Demizu ¹, Takeo Takahashi, Fumiya Kaneko, Yukiko Sato, Haruhiro Okuda, Eiji Ochiai, Kyohei Horie, Ken-Ichiro Takagi, Shinji Kakuda, Midori Takimoto-Kamimura, Masaaki Kurihara

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Affiliation

1 Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.

PMID: 21889334 DOI: 10.1016/j.bmcl.2011.08.047

Abstract

We designed and synthesized nonsecosteroidal vitamin D receptor (VDR) ligands that formed H-bonds with six amino acid residues (Tyr143, Ser233, Arg270, Ser274, His301 and His393) of the VDR ligand-binding domain. The ligand YR335 exhibited potent transcriptional activity, which was comparable to those of 1α,25-dihydroxyvitamin D(3) and YR301. The crystal structure of the complex formed between YR335 and the VDR ligand-binding domain was solved, which revealed that YR335 formed H-bonds with the six amino acid residues mentioned above.

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