MORGAN FINGERPRINT–BASED SCREENING AND DOCKING IDENTIFY CALCIFEDIOL, A SECOSTEROIDAL VITAMIN D ANALOG, AS A PROMISING FARNESOID X RECEPTOR MODULATOR IN CHOLESTATIC LIVER DISEASE

Cholestatic liver disease (CLD) encompasses a spectrum of hepatobiliary disorders characterized by impaired bile formation and accumulation of toxic bile acids, leading to hepatic injury, fibrosis, and progressive liver dysfunction. The Farnesoid X Receptor (FXR), a bile acid–activated nuclear receptor, serves as a crucial regulator of bile acid homeostasis, lipid metabolism, and inflammation. Pharmacological modulation of FXR has emerged as a promising therapeutic approach; however, existing agonists such as Obeticholic acid exhibit dose-limiting adverse effects.
In this study, Morgan fingerprint–based virtual screening was conducted using Obeticholic acid as the lead molecule to identify structurally similar analogs from the DrugBank database. The shortlisted candidates were subjected to molecular docking against FXR (PDB ID: 5Y1J) to evaluate their binding affinities and interaction profiles. Among 20 screened compounds, Calcifediol (25-hydroxyvitamin D₃) demonstrated the most favorable docking energy (–8.7 kcal/mol), surpassing the reference compound Obeticholic acid (–7.6 kcal/mol). Validation of the FXR model through PDB-REDO refinement confirmed enhanced stereochemical quality, with improved R-free values, Ramachandran plot normality, and bond geometry metrics.
Physicochemical and pharmacokinetic evaluation revealed that Calcifediol possesses a balanced lipophilic–hydrophilic profile, high gastrointestinal absorption, blood–brain barrier permeability, and compliance with major drug-likeness filters, indicating excellent pharmacological potential.
Overall, the computational findings highlight Calcifediol as a promising secosteroidal Vitamin D analog capable of modulating FXR activity. The results suggest a novel therapeutic avenue linking vitamin D metabolism with bile acid regulation, warranting further in vitro and in vivo validation for its potential use in cholestatic liver disease management.