Discovery of novel nuclear receptor modulating ligands: an integral role for peptide interaction profiling.

There is currently a marketed drug for nearly every nuclear receptor for which the natural ligand has been identified. However, because of the complexity of signal transduction by this class of ligand-regulated transcription factors, few of these drugs have been optimized for pharmaceutical effectiveness. Over the past several years, structural and biochemical work has shed light on some of the ligand-induced features of nuclear receptors that enable them to trigger signal transduction cascades. This review will highlight the use of peptide interactions to cluster different classes of ligands and to identify novel nuclear receptor-modulating ligands as potential drug candidates. Phage display and a multiplexed peptide interaction assay are two of the technologies that are key to this approach. When used as part of a drug discovery platform, this type of biochemical characterization can bridge the gap between high-throughput chemical synthesis and disease model testing. Furthermore, the development of these methodologies is timely because there is a significant medical need for new and improved nuclear receptor drugs that retain beneficial effects but do not have undesired side effect activities.