Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening

Abstract

Nuclear receptors (NRs) are fundamental regulators of several biological processes in which they are controlling the transcription of target genes in eukaryotic cells that are modulated in a ligand-dependent manner. Most ligands bind to a pocket in the interior of the ligand-binding domain. However, there is experimental evidence of the existence of alternative ligand-binding sites on the surface of the ligand-binding domain which can be addressed by small organic molecules that prevent binding of proteins essential for NR function and thereby may be used as alternative NR inhibitors for the treatment of various diseases. Mutational studies showed the importance of these sites for the functionality of the protein in vitro, and thereby validating their druggability. Although the pharmacological potency is tremendous there are no inhibitors under clinical investigation yet. This approach opens a door to develop a set of novel nuclear receptor modulators against several diseases such as cancer or diabetes. There is a large amount of structural information about the mechanism and regulation of NR and - in this sense - the implementation of computational approaches for drug screening combined with experimental high-throughput screening (HTS) technologies will be a milestone in the identification of specific NR ligand mimicking inhibitors. This project aims to use the combination of in silico and in vitro drug discovery approaches to interfere with alternative NR ligand binding sites in human cells. (AU)