A Structure-based Approach to Retinoid X Receptor-α Inhibition*

In this paper we describe a structure-based approach designed to identify novel ligands for retinoid X receptor-α (RXRα). By using a virtual approach based on a modified scoring function, we have selected 200 potential candidates on the basis of their predicted ability of docking into the ligand-binding site of the target. Subsequent experimental verification of the compounds in in vitro and cell-based assays led to the identification of a number of novel high affinity ligands for RXRα. The compounds are capable of displacing 9-cis-retinoic acid with IC50 values in the 10 nm and 5 μm range and exhibit marked antagonistic activity in cellular assays. The inhibitory scaffolds discovered with this method form the basis for the development of novel RXRα ligands with potential therapeutic properties.