title: Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane.
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.
authors: Graduate School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10, Kanda-Surugadai, Tokyo 101-0062, Japan.
authors: Shinya
authors: S
authors: Fujii
authors: Hiroyuki
authors: H
authors: Masuno
authors: Yoshiyuki
authors: Y
authors: Taoda
authors: Atsushi
authors: A
authors: Kano
authors: Angsuma
authors: A
authors: Wongmayura
authors: Makoto
authors: M
authors: Nakabayashi
authors: Nobutoshi
authors: N
authors: Ito
authors: Masato
authors: M
authors: Shimizu
authors: Emiko
authors: E
authors: Kawachi
authors: Tomoya
authors: T
authors: Hirano
authors: Yasuyuki
authors: Y
authors: Endo
authors: Aya
authors: A
authors: Tanatani
authors: Hiroyuki
authors: H
authors: Kagechika
mesh_terms: D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000187:drug effects; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001896:Boron Compounds; D008024:Ligands; D018167:Receptors, Calcitriol