A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co‐regulator Assembly

Abstract

The farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce a conformational change in FXR that modulates its binding to co‐regulators, thus resulting in distinct FXR functional profiles. However, the mechanisms for selectively recruiting co‐regulators by FXR remain elusive, partly because of the lack of FXR‐selective modulators. We report the identification of two natural terpenoids, tschimgine and feroline, as novel FXR modulators. Remarkably, their crystal structures uncovered a secondary binding pocket important for ligand binding. Further, tschimgine or feroline induced dynamic conformational changes in the activation function 2 (AF‐2) surface, thus leading to differential co‐regulator recruiting profiles, modulated by both hydrophobic and selective hydrogen‐bond interactions unique to specific co‐regulators. Our findings thus provide a novel structure template for optimization for FXR‐selective modulators of clinical value.

Farnesoid X receptor (FXR): Structures and ligands

“…These conformational changes may stabilize the overall structure of FXR-LBD and promote its affinity for coactivator binding. In addition, a second binding induced, hydrophobic pocket was reported in the crystal structures of FXR-terpenoid (PDB 5IAW and 5ICK) [43] . The first ligand occupies the binding site with similar other ligands [43] .…”

“…In addition, a second binding induced, hydrophobic pocket was reported in the crystal structures of FXR-terpenoid (PDB 5IAW and 5ICK) [43] . The first ligand occupies the binding site with similar other ligands [43] . H6 is shifted outward and H2 is also distorted to induce a second pocket to accommodate the extra terpenoid ligand perpendicular to the first one, resulting in the substantial expansion of the pocket size [43] .…”

Molecular tuning of farnesoid X receptor partial agonism

“…Differential binding modes within the FXR ligand binding site of FXR agonists OCA and MFA-1 15 , and differential effects of FXR agonists GW4064, CDCA and fexaramine on FXR regulated gene expression 16 already indicated several years ago, that FXR activation is more complex than just switched on or off. Later studies revealed that FXR ligands can differ in their recruitment profiles of various co-activators 17,18 , a characteristic that has also been observed for other NRs such as peroxisome proliferator-activated receptors 19,20 . Moreover, ivermectin 18 and structural analogues 21 were identified as specific FXR modulators that despite recruiting the NR co-repressor NCoR-2 to the FXR-LBD induced FXR-mediated reporter activity and gene expression, and recent results also point to an allosteric mechanism 22 of FXR activation by small molecules.…”

Performance of HADDOCK and a simple contact-based protein–ligand binding affinity predictor in the D3R Grand Challenge 2

“…The target of the D3R Grand Challenge 2 is the Farnesoid X nuclear receptor (FXR), which is a nuclear hormone receptor activated by bile acids [ 17 ]. FXR is highly expressed in liver, intestines and kidneys, playing an important role in the regulation of bile acid homeostasis and cholesterol, lipid and glucose metabolisms [ 17 – 19 ].…”

“…The target of the D3R Grand Challenge 2 is the Farnesoid X nuclear receptor (FXR), which is a nuclear hormone receptor activated by bile acids [ 17 ]. FXR is highly expressed in liver, intestines and kidneys, playing an important role in the regulation of bile acid homeostasis and cholesterol, lipid and glucose metabolisms [ 17 – 19 ]. Due to its involvement in various diseases including inflammatory bowel disease, colorectal cancer and type 2 diabetes, FXR agonists have emerged as potential therapeutics [ 17 – 19 ].…”