Covalent ligands of nuclear receptors

Abstract

Nuclear receptors (NRs) are ligand-induced transcriptional factors implicated in several physiological pathways. Naïve ligands bind to their cognate receptors and modulate gene expression as agonists or antagonists. It has been observed that some ligands bind via covalent bonding with the NR Ligand Binding Domain (LBD) residues. While many such instances have been known since the 1980s, a consolidated account of these ligands and their interactions with NR-LBD is yet to be documented. To negate this, we have culled out the human NR-LBDs that form a covalent attachment with ligands. According to the study, 16 of the 48 human NRs have been targeted by covalent ligands. It was found that conserved cysteines prone to covalent attachment are predominantly located in NR-LBD helices 3 and 11. These conserved cysteines are also observed in many of the remaining NRs, which can be probed for their reactivity. Thus, the structural insights into NR-LBD interactions with covalent ligands presented here would aid drug discovery efforts targeting NRs.

Keywords: Covalent drug; Drug discovery; Ligand binding domain; Nuclear receptors.