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

Abstract

Vitamin D 3 is metabolized into the hormonally active form, 1α,25-dihydroxyvitamin D 3 ( 1), via 25-hydroxyvitamin D 3 ( 2) which is the most abundant circulating metabolite. Introduction of the 1α-hydroxyl group into 25-hydroxyvitamin D 3 ( 2) to produce 1α,25-dihydroxyvitamin D 3 ( 1) increases the VDR binding affinity by approximately 1000-fold. The X-ray crystal structure of human VDR in complex with 1α,25-dihydroxyvitamin D 3 ( 1) shows that, together with Ser-237, the 1α-hydroxyl group of 1α,25-dihydroxyvitamin D 3 ( 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 1α-hydroxyl group, as well as the results with lithocholic acid and its derivatives, we designed the C2 modified analogues of 25-hydroxylvitamin D 3 ( 2) having a carboxyl group, instead of the 1-hydroxyl group, for better electrostatic interaction to the guanidinium side-chain of arginine.