Structure–activity relationship of nonsecosteroidal vitamin D receptor modulators

•The crystal structures of the vitamin D receptor with nonsecosteroidal ligands are reviewed.•Nonsecosteroidal ligands bind to the receptor in a position similar to 1,25(OH)2D3.•Hydrogen bond interactions between the receptor and ligands are important.•Hydrophobic interactions in aromatic ligands are also important.•Nonsecosteroidal ligands act as selective vitamin D receptor modulators.

The vitamin D receptor (VDR), a receptor for the secosteroid 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a promising drug target in the treatment of bone and mineral disorders, cancer, autoimmune disease, infection, and cardiovascular disease. Indeed, approximately 100 nonsecosteroidal VDR modulators (VDRMs) have been developed. Analysis of X-ray crystal structures reveals: (i) nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25(OH)2D3; (ii) hydrogen bond interactions between ligands and VDR are the most important for VDR binding; (iii) hydrophobic interactions and CH–π interactions in aromatic ligands are also important for VDR binding; and (iv) exchange of C-O-C linkage to C-CH2-C linkage in VDRMs increases transactivation activity, probably as a result of an entropic effect of solvation/desolvation of molecules. Several VDRMs have better therapeutic efficacy when compared to 1,25(OH)2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia, a major potential adverse effect in the clinical application of VDR ligands.