Structural basis of tropifexor as a potent and selective agonist of farnesoid X receptor.

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Jiang L, Xiao D, Li Y, Dai S, Qu L, Chen X, Guo M, Wei H, Chen Y

Structural basis of tropifexor as a potent and selective agonist of farnesoid X receptor.

Biochem Biophys Res Commun. 2021 Jan 1;534:1047-1052. doi: 10.1016/j.bbrc.2020.10.039. Epub 2020 Oct 26.

PubMed ID

33121679 [ View in PubMed

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Abstract

Farnesoid X receptor (FXR) is considered as a potential target for the treatment of several liver disorders such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Tropifexor is a highly potent and non-steroidal FXR agonist that has progressed into phase II clinical trials in patients with PBC. The clinical trials demonstrate that tropifexor improved serum markers of patients with liver diseases and lower side effect such as pruritus that might be implicated with TGR5 activation. However, the molecular mechanism of the potency and selectivity of tropifexor remains unclear. In this study, the binding affinity of FXR and tropifexor is measured by isothermal titration calorimetry (ITC) assays. The crystal structure of the FXR/tropifexor complex is determined at 2.7 A resolution to explain the molecular mechanism of tropifexor bound to FXR-LBD. Structural comparison with other FXR/agonists structures reveals the conformational change in the FXR/tropifexor structure. Moreover the structural superposition of TGR5/tropifexor indicates that the steric hindrance between tropifexor and TGR5 might be a possible explanation for the impotency arises of tropifexor to TGR5. Overall, our analyses might provide an insight into the molecular mechanism of tropifexor binding to FXR-LBD and account for the high selectivity of tropifexor for FXR versus TGR5.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tropifexor	Bile acid receptor	Protein	Humans	Unknown	Agonist Binder	Details