Novel vitamin D receptor ligands having a carboxyl group as an anchor to arginine 274 in the ligand-binding domain.

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Fujishima T, Tsuji G, Tanaka C, Harayama H

Novel vitamin D receptor ligands having a carboxyl group as an anchor to arginine 274 in the ligand-binding domain.

J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):60-2. doi: 10.1016/j.jsbmb.2010.04.020. Epub 2010 May 6.

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20435140 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Alfacalcidol	Vitamin D3 receptor	Protein	Humans	Yes	Agonist	Details
Cholecalciferol	Vitamin D3 receptor	Protein	Humans	Yes	Agonist	Details