Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist

• Published in: Scientific reports 2020-12, Vol.10 (1), p.22279-14, Article 22279
• Main Authors: Mays, Suzanne G., Stec, Józef, Liu, Xu, D’Agostino, Emma H., Whitby, Richard J., Ortlund, Eric A.
• Format: Article
• Language: English
• Subjects: 631/45/535/1266; 631/92/609; Agonists; Chirality; Crystal structure; Drug development; Enantiomers; GLP-1 receptor agonists; Homeodomain Proteins - chemistry; Homeodomain Proteins - genetics; Homeodomain Proteins - ultrastructure; Homeostasis; Humanities and Social Sciences; Humans; Ligands; Liver; Metabolic Diseases - drug therapy; Molecular Dynamics Simulation; multidisciplinary; Neoplasms - drug therapy; Nuclear receptors; Pharmacokinetics; Receptor mechanisms; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - ultrastructure; Recruitment; Science; Science (multidisciplinary); Stereoisomerism; Steroidogenic Factor 1 - antagonists & inhibitors; Steroidogenic Factor 1 - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-79251-9

Chirality is an important consideration in drug development: it can influence recognition of the intended target, pharmacokinetics, and off-target effects. Here, we investigate how chirality affects the activity and mechanism of action of RJW100, a racemic agonist of the nuclear receptors liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). LRH-1 and SF-1 modulators are highly sought as treatments for metabolic and neoplastic diseases, and RJW100 has one of the few scaffolds shown to activate them. However, enantiomer-specific effects on receptor activation are poorly understood. We show that the enantiomers have similar binding affinities, but RR-RJW100 stabilizes both receptors and is 46% more active than SS-RJW100 in LRH-1 luciferase reporter assays. We present an LRH-1 crystal structure that illuminates striking mechanistic differences: SS-RJW100 adopts multiple configurations in the pocket and fails to make an interaction critical for activation by RR-RJW100. In molecular dynamics simulations, SS-RJW100 attenuates intramolecular signalling important for coregulator recruitment, consistent with previous observations that it weakly recruits coregulators in vitro. These studies provide a rationale for pursuing enantiomerically pure RJW100 derivatives: they establish RR-RJW100 as the stronger LRH-1 agonist and identify a potential for optimizing the SS-RJW100 scaffold for antagonist design.