title: Novel vitamin D receptor ligands having a carboxyl group as an anchor to arginine 274 in the ligand-binding domain.
abstract: Vitamin D3 is metabolized into the hormonally active form, 1alpha,25-dihydroxyvitamin D3 (1), via 25-hydroxyvitamin D3 (2) which is the most abundant circulating metabolite. Introduction of the 1alpha-hydroxyl group into 25-hydroxyvitamin D3 (2) to produce 1alpha,25-dihydroxyvitamin D3 (1) increases the VDR binding affinity by approximately 1000-fold. The X-ray crystal structure of human VDR in complex with 1alpha,25-dihydroxyvitamin D3 (1) shows that, together with Ser-237, the 1alpha-hydroxyl group of 1alpha,25-dihydroxyvitamin D3 (1) makes hydrogen bonds with Arg-274, single mutation of which results in impaired ligand recognition. In 2002, lithocholic acid, which possesses a carboxyl group at position C24, was demonstrated to be a weak VDR ligand. We speculated that the carboxylic acid of lithocholic acid could be recognized by Arg-274 in the ligand-binding domain of VDR. In view of the significance of Arg-274 to direct the 1alpha-hydroxyl group, as well as the results with lithocholic acid and its derivatives, we designed the C2 modified analogues of 25-hydroxylvitamin D3 (2) having a carboxyl group, instead of the 1-hydroxyl group, for better electrostatic interaction to the guanidinium side-chain of arginine.
authors.affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido 1314-1, Sanuki, Kagawa 769-2193, Japan. tofu@kph.bunri-u.ac.jp
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Genichiro
authors.initials: G
authors.lastname: Tsuji
authors.forename: Chika
authors.initials: C
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harayama
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002112:Calcifediol / Q000737:chemistry; D002417:Cattle; D018360:Crystallography, X-Ray / Q000379:methods; D004353:Drug Evaluation, Preclinical; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D009154:Mutation; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry*; D055672:Static Electricity; D014807:Vitamin D / Q000737:chemistry
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D014807:Vitamin D; D001120:Arginine; D019791:Guanidine; D002112:Calcifediol