The Study Of Pharmacophore Modeling And Molecular Docking For RXR

RXRs regulate gene transcription either as homodimers (RXR:RXR) or as heterodimers with other nuclear receptors such as RARs, TR, VDR, LXR, FXR, PPARs, and NGFIB. RXRs are important targets for drug discovery, for their unique capability to interact with a variety of other nuclear receptors.Three-dimensional pharmacophore models were generated for RXR (α,β,γ) agonists and RXRαantagonists using quantitative approach (Catalyst HypoRefine). Molecular Docking for RXR (α,β) were made using DOCK software.The best quantitative model for RXRαagonists has four features and eight excluded volumes: three hydrophobic groups and one hydrogen bond receptor. DOCK result shows that a majority of the ligand is in the hydrophobic region and there are some bulk amino acids around the ligand. Ligands can form hydrogen bond with Ala332 in receptor. The pharmacophore model matches the DOCK result well.The best quantitative model for RXRαantagonists has five features and five excluded volumes: three hydrophobic groups, one aromatic ring, and one hydrogen bond receptor.The best quantitative model for RXRβagonists had four features and nine excluded volumes: two hydrophobic groups and one hydrophobic aromatic, one hydrogen bond receptor. DOCK result shows that a majority of the ligand is in the hydrophobic region and there are some bulk amino acids around the ligand. Ligands can form hydrogen bond with Ala398,Arg387 in receptor. The pharmacophore model matches the DOCK result well.The best quantitative model for RXRγagonists had five features and five excluded volumes: three hydrophobic aliphatic groups, one hydrophobic aromatic ring, and one hydrogen bond receptor.These EVs'combined effort restricts the flexibility of the compounds and thus could reflect the best conformation with which the ligands interact with the receptor.These models were validated using a wide range of test molecules. It could predict agonist or antagonist activity and identify highly potent molecules. The present results are valuable to discover and develop specific RXR (α,β,γ) agonists and RXRαantagonists with desired biological activities.