Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods

Abstract

The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode. Among them 3b and 3d are more active than the parent compound OA. A molecular simulation study was performed to attempt to explain the structure-activity relationship (SAR) and the antagonistic action. To the best of our knowledge, this is the first report on semi-synthetic pentacyclic triterpenoids with FXR-modulatory activities.

Keywords: FXR antagonist; compound diversity; library design; molecular modeling; oleanolic acid.

Figure 1

Structures of some farnesoid X receptor (FXR) agonists.

Figure 2

Structure of oleanolic acid (OA).

Figure 3

OA analogs to be synthesized.

Scheme 1

Preparation of compound 4.

Scheme 2

Synthesis of compound 3a.

Scheme 3

Synthesis of compound 3b.

Scheme 4

Synthesis of compound 3c.

Scheme 5

Synthesis of compound 3d.

Figure 4

Binding modes of fexaramine (yellow) and compound 3b (magenta) into FXR. Key residues involved in the formation of “charge clamp” and the interactions with fexaramine and compound 3b are all marked and presented as sticks. Helices discussed in the text are numbered.