Covalent ligands of nuclear receptors

被引:2
作者
Rajan, Sreekanth [1 ]
Yoon, Ho Sup [1 ,2 ,3 ]
机构
[1] Nanyang Technol Univ, Sch Biol Sci, 60 Nanyang Dr, Singapore 637551, Singapore
[2] CHA Univ, Coll Pharm, 120 Haeryong Ro, Pocheon Si 11160, Gyeonggi Do, South Korea
[3] CHA Adv Res Inst, 335 Pangyo Ro, Seongnam Si 13488, South Korea
关键词
Nuclear receptors; Ligand binding domain; Covalent drug; Drug discovery; HUMAN ESTROGEN-RECEPTOR; THYROID-HORMONE-RECEPTOR; PPAR-GAMMA; GLUCOCORTICOID-RECEPTORS; ATTACHMENT SITE; ORGANOTIN COMPOUNDS; STRUCTURAL BASIS; BINDING DOMAIN; IDENTIFICATION; CYSTEINE;
D O I
10.1016/j.ejmech.2023.115869
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Nuclear receptors (NRs) are ligand-induced transcriptional factors implicated in several physiological pathways. Naive 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.
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页数:14
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