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

• Published in: Biophysical chemistry Vol. 270; p. 106540
• Main Authors: Nakamura, Shunya, Saito, Ryosuke, Yamamoto, Shohei, Terauchi, Yuta, Kittaka, Atsushi, Takimoto-Kamimura, Midori, Kurita, Noriyuki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2021
• Subjects: Antagonist; Binding affinity; Fragment molecular orbital; In silico drug design; Inhibitor; Molecular docking; Molecular simulation; Protein ligand interaction; Vitamin D receptor; Molecular simulation; Protein ligand interaction; Vitamin D receptor; Fragment molecular orbital; Inhibitor; Antagonist; Binding affinity; In silico drug design; Molecular docking
• ISSN: 0301-4622; 1873-4200
• DOI: 10.1016/j.bpc.2020.106540

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 D3-26,23-lactone), was revealed to posse almost 1000-fold improved antagonistic activity over the original TEI-9647. However, the reason for this significant improvement has not been elucidated. In the present study, we investigated the specific interactions between VDR and these inhibitors, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations. Based on the results simulated, we furthermore proposed novel inhibitors and investigated their binding properties to VDR. The results elucidate that the replacement of propyl group at the 24th site of NS-54c by a phenethyl group can enhance the binding affinity of the inhibitor to VDR. This finding provides useful information for developing novel potent inhibitors against VDR. [Display omitted] •We proposed novel inhibitors for vitamin-D receptor (VDR) by molecular simulations.•Molecular-docking, MM optimization and fragment MO simulations were used.•3-hydroxypropoxy group at the 2α site of NS-54c is important for binding to VDR.•This group forms strong hydrogen bonds with Tyr236 and Asp144 of VDR.•Replacement of the propyl group by the phenethyl group enhances the binding to VDR.