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Gene Regulatory Potential of Nonsteroidal Vitamin D Receptor Ligands

Departments of Chemistry (M.P.) and Biochemistry (M.M., C.C.), A. I. Virtanen Institute (K.-H.H.), University of Kuopio, FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Prof. Carsten Carlberg, Department of Biochemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: carlberg{at}messi.uku.fi.

The seco-steroid 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] is a promising drug candidate due to its pleiotropic function including the regulation of calcium homeostasis, bone mineralization and cellular proliferation, differentiation, and apoptosis. We report here a novel class of nonsteroidal compounds, represented by the bis-aromatic molecules CD4409, CD4420, and CD4528, as ligands of the 1,25(OH)₂D₃ receptor (VDR). Taking the known diphenylmethane derivative LG190178 as a reference, this study provides molecular evaluation of the interaction of nonsteroidal ligands with the VDR. All four nonsteroidal compounds were shown to induce VDR-retinoid X receptor heterodimer complex formation on a 1,25(OH)₂D₃ response element, stabilize the agonistic conformation of the VDR ligand-binding domain, enable the interaction of VDR with coactivator proteins and contact with their three hydroxyl groups the same residues within the ligand-binding pocket of the VDR as 1,25(OH)₂D₃. Molecular dynamics simulations demonstrated that all four nonsteroidal ligands take a shape within the ligand-binding pocket of the VDR that is very similar to that of the natural ligand. CD4528 is mimicking the natural hormone best and was found to be in vitro at least five times more potent than LG190178. In living cells, CD4528 was only two times less potent than 1,25(OH)₂D₃ and induced mRNA expression of the VDR target gene CYP24 in a comparable fashion. At a noncalcemic dose of 150 µg/kg, CD4528 showed in vivo a clear induction of CYP24 expression and therefore may be used as a lead compound for the development of therapeutics against psoriasis, osteoporosis, and cancer.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Coregulators:   GRIP1

Ligands:   Calcitriol