Small Molecule Compounds Design Based On Nuclear Receptor Target And Its Chemical Biology Research

Retinoid X receptors ?(RXR?) is a member of the nuclear receptor superfamily and can selectively combine with ligands to modulate cells physiological effects. RXR? can form homodimers with themselves or heterodimers with other nuclear receptors. RXR? is connected with metabolism, growth, development, differentiation, death and immune. Thus, targeting RXR? has been considered as one of the effective strategies for the treatment of metabolic diseases and cancer. So far, 9-cis-RA is the natural ligand which can combine with RXR?. Synthetic ligands are also not that much. Therefore, the purpose of our research is to design and synthesize a series of compounds according to the structural characteristics of RXR?, and screening novel small molecule compounds which can binding to RXR?.In our research, we obtained higher yield of RXR?-LBD protein by optimizing the RXR? receptor protein extraction conditions. Then screened the existing compounds of laboratory by Biacore technology(Surface Plasmon Resonance, SPR) to obtain 6 compounds which can bind to RXR?-LBD protein and measure their dissociation equilibrium constant KD values. Further study was taken by ITC(Isothermal Titration Calorimetry) technology to test 6 molecule compounds. After improvement and optimization of ITC experimental methods, we finally obtained 2 small molecular compounds, WH-30 and WH-15, which have good dissociation equilibrium constant KD values, and very close to Biacore experimental results. The thermodynamic parameters obtained by ITC demonstated that WH-30 and WH-15 combining with RXR?-LBD protein was a spontaneous exothermic reaction. At last, we used AutoDock 4.2.5 software to do molecular docking between WH-30, WH-15 and RXR?-LBD homodimer(PDB ID: 4N5G). We can get the binding energies and molecular docking figures by molecular docking, and both of them indicated that molecular compounds WH-30 and WH-15 can bind to RXR? receptor.