Sciren Staff Lv 1
LRH-1 (liver receptor homologue-1) and SF-1 (steroidogenic factor 1) are nuclear receptors, meaning they behave like sensors that translate signals to control what genes are turned on and off. LRH-1 regulates metabolism by controlling the balance of fat and sugar production. Researchers have used synthetic compounds to modify LRH-1 activity such that the symptoms of inflammatory bowel disease and diabetes are alleviated in mice. SF-1 is critical for hormone balance, controlling steroid production and associated with obesity. SF-1 is also important in reproduction, and is a proposed therapeutic target for endometriosis. Both LRH-1 and SF-1 are also related to several cancers, including the rare and deadly adrenocortical carcinoma, plus breast, pancreatic, gastrointestinal, and endometrial cancers.
Noting the therapeutic potential for these targets, there has been substantial effort to develop drugs that bind to these receptors. However, to date there are no FDA-approved drugs for either target.
“Undruggable targets”
LRH-1 and SF-1 are considered undruggable targets due to their large and flexible ligand binding pockets, which make it difficult for drug-like compounds to bind tightly and specifically. Researchers think that lipids (fat-like molecules) are the natural ligands that bind to the LRH-1 and SF-1 and signal changes in activity. Lipids are much larger than drug-like compounds and possess different chemical and physiological properties, therefore developing synthetic molecules that can act in place of lipids is difficult. Another problem is that both receptors can become active without a bound ligand, therefore controlling their activity may be more difficult than a clear on/off switch. A third problem is that both LRH-1 and SF-1 are structurally very similar to each other and therefore same compounds often bind to both targets. Finding drugs that are selective enough to bind to one target and not the other is necessary to avoid unintended side effects.
The starting models
The starting models for the puzzle series are LRH-1 (PDB code 7TT8) and SF-1 (PDB code 8DAF), each bound to the synthetic agonist 6N-10CA. The compound binds strongly to both and activates both results. In laboratory tests this compound can control the activity of LRH-1 and SF-1 and therefore change what genes are expressed. However, the chemical properties of 6N-10CA do not make it a good candidate to be developed into a commercial drug. Researchers at the Meiler and Blind labs at VU/VUMC and other scientists have performed extensive screening efforts searching for new compounds that will bind to SF-1 and LRH-1. While we have found potential candidates, 6N-10CA remains the best compound with structural models. The model provide valuable insight into how the compound interacts with each target and serves as a starting point for drug discovery and design efforts.
The task:
Drug the undruggable! Build off of the known binders and try to come up with molecules that bind to these receptors, fill up the ligand binding pocket space, and are more drug-like. As the weeks progress we will explore pocket structure (conformation) and different starting molecules.
Literature:
Krylova, I. N.; Sablin, E. P.; Moore, J.; Xu, R. X.; Waitt, G. M.; MacKay, J. A.; Juzumiene, D.; Bynum, J. M.; Madauss, K.; Montana, V.; Lebedeva, L.; Suzawa, M.; Williams, J. D.; Williams, S. P.; Guy, R. K.; Thornton, J. W.; Fletterick, R. J.; Willson, T. M.; Ingraham, H. A. Structural Analyses Reveal Phosphatidyl Inositols as Ligands for the NR5 Orphan Receptors SF-1 and LRH-1. Cell 2005, 120 (3), 343–355.
Whitby, R. J.; Stec, J.; Blind, R. D.; Dixon, S.; Leesnitzer, L. M.; Orband-Miller, L. A.; Williams, S. P.; Willson, T. M.; Xu, R.; Zuercher, W. J.; Cai, F.; Ingraham, H. A. Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2). J Med Chem 2011, 54 (7), 2266–2281.
Lang, A.; Isigkeit, L.; Schubert-Zsilavecz, M.; Merk, D. The Medicinal Chemistry and Therapeutic Potential of LRH-1 Modulators. J Med Chem 2021, 64 (23), 16956–16973. https://doi.org/10.1021/acs.jmedchem.1c01663
Cato, M. L.; D’Agostino, E. H.; Spurlin, R. M.; Flynn, A. R.; Cornelison, J. L.; Johnson, A. M.; Fujita, R. A.; Abraham, S. M.; Jui, N. T.; Ortlund, E. A. Comparison of Activity, Structure, and Dynamics of SF-1 and LRH-1 Complexed with Small Molecule Modulators. Journal of Biological Chemistry 2023, 299 (8).
