Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: Direct observation of hydrophobic interaction between protein surface and carborane

Shinya Fujii, Hiroyuki Masuno, Yoshiyuki Taoda, Atsushi Kano, Angsuma Wongmayura, Makoto Nakabayashi, Nobutoshi Ito, Masato Shimizu, Emiko Kawachi, Tomoya Hirano, Yasuyuki Endo, Aya Tanatani, Hiroyuki Kagechika

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo- dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.

Original languageEnglish
Pages (from-to)20933-20941
Number of pages9
JournalJournal of the American Chemical Society
Volume133
Issue number51
DOIs
Publication statusPublished - Dec 28 2011
Externally publishedYes

Fingerprint

Calcitriol Receptors
Boron
Vitamins
Hydrophobic and Hydrophilic Interactions
Membrane Proteins
Ligands
Observation
Proteins
Flexible structures
Drug Design
Vitamin D
Hydroxyl Radical
Hormones
Chemical stability
Binding sites
Carbon
Hot Temperature
Anchors
Binding Sites
X-Rays

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands : Direct observation of hydrophobic interaction between protein surface and carborane. / Fujii, Shinya; Masuno, Hiroyuki; Taoda, Yoshiyuki; Kano, Atsushi; Wongmayura, Angsuma; Nakabayashi, Makoto; Ito, Nobutoshi; Shimizu, Masato; Kawachi, Emiko; Hirano, Tomoya; Endo, Yasuyuki; Tanatani, Aya; Kagechika, Hiroyuki.

In: Journal of the American Chemical Society, Vol. 133, No. 51, 28.12.2011, p. 20933-20941.

Research output: Contribution to journalArticle

Fujii, S, Masuno, H, Taoda, Y, Kano, A, Wongmayura, A, Nakabayashi, M, Ito, N, Shimizu, M, Kawachi, E, Hirano, T, Endo, Y, Tanatani, A & Kagechika, H 2011, 'Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: Direct observation of hydrophobic interaction between protein surface and carborane', Journal of the American Chemical Society, vol. 133, no. 51, pp. 20933-20941. https://doi.org/10.1021/ja208797n
Fujii, Shinya ; Masuno, Hiroyuki ; Taoda, Yoshiyuki ; Kano, Atsushi ; Wongmayura, Angsuma ; Nakabayashi, Makoto ; Ito, Nobutoshi ; Shimizu, Masato ; Kawachi, Emiko ; Hirano, Tomoya ; Endo, Yasuyuki ; Tanatani, Aya ; Kagechika, Hiroyuki. / Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands : Direct observation of hydrophobic interaction between protein surface and carborane. In: Journal of the American Chemical Society. 2011 ; Vol. 133, No. 51. pp. 20933-20941.
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