2026-04-18T02:22:57Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/534872025-12-12T03:52:46Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Mays, Suzanne G. author Stec, Józef author Liu, Xu author D'Agostino, Emma H. author Whitby, Richard J. author Ortlund, Eric A. author 2022-06-14T09:05:25Z 2022-06-14T09:05:25Z 2020 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. This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM008602 to SGM], National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant F31-DK111171 to SGM, Grants R01-DK095750 and R01-DK114213 to EAO], the National Science Foundation [Grant DGE-1444932 to EHD], the American Heart Association [Grant 17POST33660110 to XL], and an Emory Catalyst Grant to EAO. RJW and JS thank GlaxoSmithKline for generous funding Quiralitat Medicaments -- Desenvolupament Fetge -- Malalties Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist