ABSTRACT
Vitamin K2 is a ligand for a nuclear receptor, steroid and xenobiotic receptor (SXR), that induces the gene expressions of CYP3A4. We synthesized new vitamin K analogues with the same isoprene side chains symmetrically introduced at the 2 and 3 positions of 1,4-naphthoquinone and vitamin K2 analogues with hydroxyl or phenyl groups at the ω-terminal of the side chain. The upregulation of SXR-mediated transcription of the target gene by the analogues was dependent on the length of the side chain and the hydrophobicity of the ω-terminal residues. Phenyl analogue menaquinone-3 was as active as the known SXR ligand rifampicin.
Subject(s)
Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Steroid/agonists , Vitamin K/chemistry , Humans , Ligands , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/genetics , Receptors, Steroid/metabolism , Structure-Activity Relationship , Vitamin K/analogs & derivatives , Vitamin K/genetics , Vitamin K/pharmacology , Xenobiotics/chemistry , Xenobiotics/metabolismABSTRACT
Vitamin K(2) has been demonstrated to induce gene expression related to bone formation through a nuclear steroid and xenobiotic receptor (SXR). We synthesized new vitamin K analogues with the same isoprene side chains symmetrically introduced at the 2 and 3 positions of 1,4-naphthoquinone and evaluated the transcriptional activity of the target gene. The transcriptional activity was related to the length of the side chain which allowed optimal interaction with ligand-binding domain of SXR.
Subject(s)
Receptors, Steroid/agonists , Vitamin K/analogs & derivatives , Vitamin K/chemical synthesis , Binding Sites , Butadienes/chemical synthesis , Butadienes/chemistry , Butadienes/pharmacology , Genes, Reporter , Hemiterpenes/chemical synthesis , Hemiterpenes/chemistry , Hemiterpenes/pharmacology , Hep G2 Cells , Humans , Ligands , Luciferases/biosynthesis , Luciferases/genetics , Pentanes/chemical synthesis , Pentanes/chemistry , Pentanes/pharmacology , Pregnane X Receptor , Receptors, Steroid/genetics , Structure-Activity Relationship , Transcription, Genetic/drug effects , Vitamin K/pharmacologyABSTRACT
We used an in silico computational method to theoretically analyze important residue-ligand interactions as well as ligand conformation changes in the vitamin D receptor (VDR). The ligand used for analysis was 1alpha,25-dihydroxy-19-nor-vitamin D3 [1alpha,25-19-nor-(OH)2D3] [1,2], whose crystal structure has not been solved. To estimate amino acid residue-ligand interactions with chemical accuracy, we adopted the fragment molecular orbital (FMO) method [3,4], which is based on the nonempirical total electronic quantum calculation. The docking of the ligand to the VDR was controlled by hydrophilic and hydrophobic interactions between amino acid residues and the ligand in the ligand binding pocket (LBP) [5-8]. These molecular interactions changed when the conformation of the ligand in the VDR was changed [5,9,10]. This conformation change is important to consider in computational, in silico, approaches for analyzing the mechanism of ligand-docking to the VDR. The position of the 1alpha,25-19-nor-(OH)2D3 ligand in the VDR-LBP was related to the hydrophobic interaction that occurred between the Ile271 residue of the VDR-LBP and the ligand. The interaction between Ile271 and 1alpha,25-19-nor-(OH)2D3 was repulsive, whereas, that between Ile271 and the natural ligand, 1alpha,25-(OH)2D3, is stable. The orientation change in the isopropyl group of Ile271 affected the residue's interaction with 1alpha,25-19-nor-(OH)2D3. We also found that conformation changes in the A-ring affected electrostatic (hydrophilic) interactions between the VDR and the ligand.
