Proposal of novel inhibitors for vitamin-D receptor: Molecular docking, molecular mechanics and ab initio molecular orbital simulations.

The specific binding of active vitamin-D to the vitamin-D receptor (VDR) is closely related to the onset of immunological diseases. To inhibit the binding, various compounds have been developed as potent inhibitors against VDR. Among them, a compound NS-54c, which was developed based on the first VDR antagonist TEI-9647 (25-dehydro-1α-hydroxyvitamin D-26,23-lactone), was revealed to posse almost 1000-fold improved antagonistic activity over the original TEI-9647.

Structural change of retinoic-acid receptor-related orphan receptor induced by binding of inverse-agonist: Molecular dynamics and molecular orbital simulations.

To elucidate structural changes in the retinoic acid receptor-related orphan receptor gamma (RORγt) induced by the binding of an agonist or an inverse agonist, we conducted molecular dynamics (MD) simulations in explicit water. In addition, fragment molecular orbital calculations were carried out for certain characteristic structures obtained from the MD simulations to reveal important interactions between the amino acid residues of RORγt, and to distinguish the different effects in the binding of an agonist and an inverse agonist on the structure of RORγt. The results elucidate that the hydrogen bond between His479 of helix11 (H11) and Tyr502 of helix12 (H12) is important to keep the H12 conformation in the agonist-bound RORγt.

Ligand chirality can affect histidine protonation of vitamin-D receptor: ab initio molecular orbital calculations in water.

Vitamin D is recognized to play important roles in the onset of immunological diseases as well as the regulation of the amount of Ca in the blood. Since these physiological actions caused by active vitamin D are triggered by the specific interaction between the vitamin D receptor (VDR) and active vitamin D, many types of compounds have been developed as potent ligands against VDR. It was found that the binding affinity between VDR and its ligand depends significantly on the chirality of the ligand.