Nuclear Receptor Screening Libraries

Nuclear receptors are a class of proteins responsible for sensing steroid and thyroid hormones and other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the organism's development, homeostasis, and metabolism of the organism. Nuclear hormone receptors are important drug targets for the treatment of a whole range of disorders, in particular inflammatory diseases, cancer, obesity, diabetes, etc. [1-2].

Life Chemicals has developed two dedicated Nuclear Receptor Screening Libraries for drug discovery screening projects:

• Nuclear Receptor Focused Library (31,900 compounds)
• Nuclear Receptor Targeted Library (12,800 compounds)

The compound selection can be customized based on your requirements, cherry-picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Nuclear Receptor Focused Library by 2D Similarity

This ligand-based Screening Set has been prepared based on 2D fingerprint similarity search against HTS Compound Collection using the reference set of data for nuclear receptors and their complex bioactivities, referring to the ChEMBL database. The minimum Tanimoto index > 0.85 allowed for the identification of over 68,000 structural analogs of reported nuclear receptor modulators. The resulting screening compound selection was reduced by dissimilarity to result in more than 31,900 drug-like small molecules for such targets as:

Representative compounds from the Life Chemicals Nuclear Receptor Ligand-Based Library by 2D Similarity

F6660-4374

F6548-2535

F3407-3637

F3055-0550

F2173-0854

F0001-2416

F2173-0138

F6548-4358

F6610-0335

F6556-6395

F6564-3818

F2073-0006

F1879-0044

F0684-0030

F6795-0844

F1436-0288

F6660-2921

F1604-0672

Nuclear Receptor Targeted Library by Docking

This Screening Set aimed at doing nuclear receptor research comprises more than 12,800 small-molecule compounds selected by protein-ligand docking method from the proprietary HTS Compound Collection. For this purpose, the Glide software from Schrödinger was applied. Several H-bond and hydrophobic constraints were assigned, that in combination with electrostatic maps of the binding sites, have been used as docking/screening models (Fig. 1) based on available crystal structures of the following nuclear receptors:

To estimate the efficiency of the docking procedure, each model was validated employing a reference set (50 to 1,100 compounds, depending on the target) with the known nuclear receptor antagonist activity (IC50 lower than 1 µM), as well as a random set of inactive compounds, both extracted from the ChEMBL database. After in silico screening, molecules with unwanted structures were excluded by means of the PAINS and our in-house medchem filters. The screening compounds within this selection are ranked as based on docking score values obtained from a docking reference set.

A	B

Fig. 1. Ligand positions and conformations generated as based on docking results. For an example, the localization of ligand molecules  from the Life Chemicals HTS Compound Collection (F3260-0084 and) are shown in the receptor binding sites (A: compound F3260-0084, estrogen; B: compound F3161-0400, progesterone).

This Library has recently been expanded with compounds selected by means of screening against the targets shown below, with this approach being built on the pharmacophore hypothesis, taking into account the ligand-protein complex:

• Nuclear receptor subfamily 4immunitygroup A member (NR4A1)
• Nuclear receptor subfamily 5 group A member 2 (NR5A2)

Nuclear receptor subfamily 4immunitygroup A member (NR4A1)

NR4A1, an orphan nuclear receptor, plays a pivotal role in various physiological processes within the human body. It serves as a key component of the Hippo pathway, contributing to the maintenance of tissue equilibrium and the control of organ size through the regulation of cell proliferation and apoptosis. This unique role makes it an attractive target for cancer therapy, particularly in the context of hepatocellular carcinoma [3]. NR4A1 also exerts its influence by inhibiting RNA Pol II transcription elongation, which turns it into a potential therapeutic target for breast cancer treatment [4]. Additionally, NR4A1 acts as a negative regulator of intestinal fibrosis by modulating myofibroblast function, which has implications for the treatment of fibrotic conditions [5].

In immunotherapy, NR4A1 emerges as a key regulator in inducing T-cell dysfunction, positioning it as a promising target for strategies aimed at combating tumor-related immune dysfunction [6]. Furthermore, NR4A1 plays a significant role in the regulation of energy balance, as well as carbohydrate and lipid metabolism. As such, it represents a potential target for addressing conditions associated with metabolic disorders [7].

Key features:

• Method: Pharmacophore-based virtual screening
• X-Ray data used: RCSB PDB ID - 3V3Q
• Filters used: no
• Number of compounds selected: 3,557

Figure 2. Pharmacophore hypothesis based on the complex of NR4A1 with inhibitor.

Nuclear receptor subfamily 5 group A member 2 (NR5A2)

NR5A2, a nuclear receptor, plays a crucial role in regulating the expression of genes involved in a wide range of biological processes. These processes encompass bile acid synthesis, cholesterol maintenance, triglyceride synthesis, embryonic stem cell pluripotency, steroidogenesis, embryo development, differentiation, and adult homeostasis [8-9]. Furthermore, NR5A2 can influence the expression of various oncogenes, thus impacting several types of cancer [10]. This receptor is also implicated in numerous physiological and pathological processes associated with the pancreas [11]. Moreover, NR5A2 influences the proliferation and differentiation of neurons, promoting axon growth [12].

Due to its multifaceted involvement in these critical processes, NR5A2 emerges as a highly promising target for therapeutic interventions to treat cancer and other diseases.

Key features:

• Method: Pharmacophore-based virtual screening
• X-Ray data used: RCSB PDB ID - 6OQX
• Filters used: no
• Number of compounds selected: 6,640

Figure 3. Pharmacophore hypothesis based on the complex of NR5A2 with inhibitor.

References:

1. Qiu T, Wu D, Qiu J, Cao Z. Finding the molecular scaffold of nuclear receptor inhibitors through high-throughput screening based on proteochemometric modeling. J Cheminform. 2018;10(1):21. Published 2018 Apr 12. doi:10.1186/s13321-018-0275-x
2. Weikum ER, Liu X, Ortlund EA. The nuclear receptor superfamily: A structural perspective. Protein Sci. 2018;27(11):1876-1892. doi:10.1002/pro.3496
3. He L, Yuan L, Yu W, et al. A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis. Cell Rep. 2020;33(3):108284. doi:10.1016/j.celrep.2020.108284
4. Guo H, Golczer G, Wittner BS, et al. NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer. Mol Cell. 2021;81(19):4041-4058.e15. doi:10.1016/j.molcel.2021.09.016
5. Pulakazhi Venu VK, Alston L, Iftinca M, et al. Nr4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2021;321(3):G280-G297. doi:10.1152/ajpgi.00338.2019
6. Liu X, Wang Y, Lu H, et al. Genome-wide analysis identifies NR4A1 as a key mediator of T-cell dysfunction. Nature. 2019;567(7749):525-529. doi:10.1038/s41586-019-0979-8
7. Zhang L, Wang Q, Liu W, Liu F, Ji A, Li Y. The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases. J Diabetes Res. 2018;2018:9363461. Published 2018 Jun 14. doi:10.1155/2018/9363461
8. Venteclef N, Jakobsson T, Ehrlund A, et al. GPS2-dependent corepressor/SUMO pathways govern the anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response. Genes Dev. 2010;24(4):381-395. doi:10.1101/gad.545110
9. Sandhu N, Rana S, Meena K. Nuclear receptor subfamily 5 group A member 2 (NR5A2): role in health and diseases. Mol Biol Rep. 2021;48(12):8155-8170. doi:10.1007/s11033-021-06784-1
10. Guo F, Zhou Y, Guo H, Ren D, Jin X, Wu H. NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15. Cell Death Discov. 2021;7(1):78. Published 2021 Apr 13. doi:10.1038/s41420-021-00462-8
11. Sun YM, Zheng S, Chen X, Gao F, Zhang J. Lower Nr5a2 Level Downregulates the β-Catenin and TCF-4 Expression in Caerulein-Induced Pancreatic Inflammation. Front Physiol. 2020;10:1549. Published 2020 Jan 9. doi:10.3389/fphys.2019.01549
12. Tsampoula M, Tarampoulous I, Antoniadou I, et al. Nuclear Receptor NR5A2 Promotes Neuronal Identity in the Adult Hippocampus. Mol Neurobiol. 2021;58(5):1952-1962. doi:10.1007/s12035-020-02222-8