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 language | English |
|---|---|
| Pages (from-to) | 20933-20941 |
| Number of pages | 9 |
| Journal | Journal of the American Chemical Society |
| Volume | 133 |
| Issue number | 51 |
| DOIs | |
| Publication status | Published - Dec 28 2011 |
| Externally published | Yes |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands
T2 - Direct observation of hydrophobic interaction between protein surface and carborane
AU - Fujii, Shinya
AU - Masuno, Hiroyuki
AU - Taoda, Yoshiyuki
AU - Kano, Atsushi
AU - Wongmayura, Angsuma
AU - Nakabayashi, Makoto
AU - Ito, Nobutoshi
AU - Shimizu, Masato
AU - Kawachi, Emiko
AU - Hirano, Tomoya
AU - Endo, Yasuyuki
AU - Tanatani, Aya
AU - Kagechika, Hiroyuki
PY - 2011/12/28
Y1 - 2011/12/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84555195210&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84555195210&partnerID=8YFLogxK
U2 - 10.1021/ja208797n
DO - 10.1021/ja208797n
M3 - Article
C2 - 22066785
AN - SCOPUS:84555195210
VL - 133
SP - 20933
EP - 20941
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 51
ER -