Orphan nuclear receptors as targets for drug development

Abstract

Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs.

Fig. 1

Classification of NR superfamily based on the identification of their respective ligands. This includes the classical NRs with known high affinity hormonal ligands, orphan receptors with no known identifiable ligands and adopted orphan receptors with low affinity dietary ligands.

Fig. 2

Schematic diagram describing classical NR function: NR binds to its ligand in the cytoplasm, which leads to its translocation into the nucleus. Ligand-bound NR dimerizes with its obligate partner to bind to the target gene regulatory element, with further recruitment of coactivators and RNA polymerase complex in the nucleus. This leads to target gene transcription with more protein production in the cytoplasm for gene specific activity.

Fig. 3

Structural domain of the NR superfamily: extreme amino terminal domain is called the A/B domain that contains the AF1 region, followed by the conserved DNA binding domain (DBD), and linked by a hinge region with the ligand binding domain (LBD). The extreme carboxy terminal end of LBD is called the AF2 region.

Fig. 4

Schematic diagrams of various drug discovery tools. Detailed descriptions of each can be found in the text.