Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Abstract

The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.

Pharmacological use of a novel scaffold, anomeric N,N-diarylamino tetrahydropyran: molecular similarity search, chemocentric target profiling, and experimental evidence

“…Among the general operators to fuse scores, multiplication is sensitive to the change in each value less or more than score 1 for PS to maximize the difference between the VDR query (CHEMBL1181633) and others 35 , 36 . The reason why only the top similar compounds are able to discriminate the real VDR ligand with non-ligands is proposed next: (1) the number of binding sites for VDR inhibitors may be more than the three sites reported until today 37 ; (2) the properties of binding sites may be very distinct (e.g., the available length, width, and height of a binding site for ligands; electrostatic environment of pockets; and shape of binding cavity); (3) possibility of indirect regulators existing in the VDR dataset.…”

“… 47 ; h PAINS: it was treated under J. B. Baell’s Knime workflow 38 ; j noticed dialkyl aniline is due to highly problematic in AlphaScreen technology (as a potent quenchers of singlet oxygen), not general ‘Pan Assay Interference Compound’ 37 .…”

“…Based on high similar VDR ligands with the compound 10 , possibility of direct binding also can’t be discarded. If the compound 10 bind to VDR, three binding regions was reported 37 . Among orthosteric binding x-ray ligands, the PDB including the most similar ligand with the compound 10 was chosen and docking of the compound 10 in the PDB (3AZ1) shows high docking score and slightly advance ligand efficient rather than the original ligand (Supplementary Figure 2 ) 51 .…”

“…Among orthosteric binding x-ray ligands, the PDB including the most similar ligand with the compound 10 was chosen and docking of the compound 10 in the PDB (3AZ1) shows high docking score and slightly advance ligand efficient rather than the original ligand (Supplementary Figure 2 ) 51 . Else, after checking co-activator binding site of VDR, compound 10 can also be used as a tool compound to find a new binding site 37 .…”

Epigenome-wide association study reveals a molecular signature of response to phylloquinone (vitamin K1) supplementation

“…NCOR2 (also known as SMRT) codes for a nuclear receptor co-repressor involved in transcriptional silencing of certain genes [15]. The protein, NCoR, is one of the most well-studied co-repressors with respect to the vitamin D receptor and also signals alongside the vitamin A-responsive RAR/RXR [16]. Though we are not aware of any involvement of NCoR in phylloquinone metabolism, the present findings combined with its connection to fat-soluble vitamin signaling could warrant further investigation.…”