Docking, Screening and Selectivity Prediction for Small- molecule Nuclear Receptor Modulators

Nuclear receptors (NRs) represent a family of ligand-dependent transcription factors, united by common functional mechanism and domain architecture. At least 13% of marketed drugs target NRs. The two key domains, the ligandbinding domain (LBD) and the DNA-binding domain (DBD), are conserved in most NRs and are surrounded by the more variable regions (N-terminal, hinge region and C-terminal domains). NR LBDs recognize, sometimes with picomolar affinity, small membrane-diffusible endogenous hormones, metabolites or xenobiotics. A ligand binding event induces reorganization of complex intraand intermolecular interactions, which ultimately leads to the formation of a complex between the NR DBD and the hormone response element of the target DNA and consequently to either initiation or repression of the target gene transcription. Nuclear receptors are found in metazoans