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

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 tho...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-10, Vol.21 (20), p.6104-6107
Main Authors: Demizu, Yosuke, Takahashi, Takeo, Kaneko, Fumiya, Sato, Yukiko, Okuda, Haruhiro, Ochiai, Eiji, Horie, Kyohei, Takagi, Ken-ichiro, Kakuda, Shinji, Takimoto-Kamimura, Midori, Kurihara, Masaaki
Format: Article
Language:English
Subjects:
amino acids
Animals
Biological and medical sciences
crystal structure
Crystallography, X-Ray
Drug Design
Ligands
Medical sciences
Miscellaneous
Models, Molecular
Nonsecosteroidal ligand
Pharmacology. Drug treatments
Protein Binding
Rats
Receptors, Calcitriol - chemistry
Receptors, Calcitriol - metabolism
transcription (genetics)
vitamin D
Vitamin D receptor
X-ray crystallographic analysis
X-ray diffraction
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.08.047