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As an experienced expert in PROTAC technology, Creative Biolabs is committed to providing first-class ligand design services targeting various disease-related proteins.
Nuclear receptors (NRs) are a class of ligand-dependent transcriptional regulatory proteins that belong to the nuclear receptor family or the steroid hormone receptor superfamily. They have homology in primary structure and gene structure. Nuclear receptors are composed of three types of receptors: a) steroid hormone receptors (SR), including glucocorticoid receptors (GR), mineralocorticoid receptors (MR), progesterone receptors (PR), androgen receptor (AR), estrogen receptors ( ER), and 1,25- (OH)2 vitamin D3 receptor; b) thyroxine receptor (TR); c) retinoic acid receptor (RAR).
As a transcriptional regulatory protein, a nuclear receptor, after binding to a corresponding ligand, interacts with a specific DNA sequence in the target gene to regulate the expression of a hormone-responsive element (HRE), resulting in a biological effect. Since nuclear receptors can regulate the expression of specific genes, when they are missing, reduced or structurally abnormal for various reasons, various diseases will be induced, namely nuclear receptor diseases. This type of disease is manifested in the resistance of target cells to the corresponding hormones.
The structure of the nuclear receptors is modular, including the N-terminal regulatory domain, DNA binding domain (DBD), hinge region, ligand binding domain (LBD), and C-terminal domain.
Fig.1 Structure of nuclear receptors.
In view of the role of NRs in physiological processes and since NRs naturally contain hydrophobic pockets that can bind small hydrophobic molecules (most effective drugs are small hydrophobic molecules), NRs are a very popular class of drug targets. Therefore, the determination of natural or synthetic ligands of NRs has attracted much attention from scientists.
Fig.2 Tree of life, nuclear receptors, and potential ligand precursors. (Frances, 2011)
Ligands bound to nuclear receptors are usually lipophilic substances, such as endogenous hormones, fatty acids, exogenous endocrine disruptors, antibiotics, and the like. Based on the structural characteristics of NRs and NRs ligands, a basic criterion when designing ligands for NRs is that compounds can bind to the ligand-binding pockets of NRs. In addition, it has been found empirically that some hydrophobic compounds can also bind to the surface of NRs. For drug development, reversible binding is often considered ideal. Based on the consideration of drugability, structural modification and modification of existing NR ligands is also an efficient strategy.
Creative Biolabs has long-term devoted to the development of PROTAC. Our scientists are confident in offering the best and most suitable ligand design solution for our customers all over the world. If you are considering developing a novel PROTAC against the target of interest, please do not hesitate to contact us for more details.