Proposal of potent inhibitors for vitamin-D receptor based on ab initio fragment molecular orbital calculations.

Vitamin D plays an important role in the regulation of the calcium and phosphorus metabolism as well as in bone formation. These physiological actions caused by vitamin D are triggered by the specific binding of vitamin D to its receptor (VDR). Here we investigated the specific interactions and binding affinities between VDR and vitamin D derivatives, using ab initio fragment molecular orbital (FMO) calculations. The FMO results elucidate that relative position of the two hydroxyl groups of the derivatives is essential for the strong binding affinity between the derivative and Arg274 residue of VDR. It is therefore expected that novel potent ligands, which have a great binding affinity for VDR, are developed by adjusting the positions of the hydroxyl groups in the derivatives in such a way as these groups form strong hydrogen bonds with VDR residues. We proposed these novel derivatives and investigated their specific interactions with VDR at atomic and electronic levels to obtain a more potent ligand for VDR.