Binding Mechanism of the Farnesoid X Receptor Marine Antagonist Suvanine Reveals a Strategy To Forestall Drug Modulation on Nuclear Receptors. Design, Synthesis, and Biological Evaluation of Novel Ligands

摘要: Here, we report suvanine, a marine sponge sesterterpene, as an antagonist of the mammalian bile acid sensor farnesoid-X-receptor (FXR). Using suvanine template, shed light on molecular bases FXR antagonism, identifying essential conformational changes responsible for transition from agonist to form. Molecular characterization nuclear corepressor NCoR and coactivator Src-1 revealed that receptor are associated with specific dynamic recruitment these cofactors promoter OSTα, regulated gene. novel hit, library semisynthetic derivatives has been designed prepared, leading pharmacological profiles ranging agonism antagonism toward FXR. Deep evaluation demonstrated derivative 19 represents new chemotype modulator, whereas alcohol 6, simplified scaffold, exhibits excellent antagonistic activity.