Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design
Year: 2019
Type: article
Abstract: As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, liver receptor homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases (IBD). Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of IBD, the new agonist increases expression of LRH-1-controlled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: green
Funders: U.S. Department of Agriculture, Emory University, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Argonne National Laboratory
Awards: Targeting LRH-1 - Phospholipid Signaling in Metabolic Pathways, Regulation of LRH-1 by small molecules, A pilot study to target out-of-dialysis-unit versus dialysis-unit blood pressure, G7244895262, G8062246797, G9000161293, Targeting the orphan nuclear receptor LRH-1 with small molecules, Texas Medical Center Digestive Diseases Center, Graduate Training in the Pharmacological Sciences
OpenAlex ID: W2967243590