Rational design of FXR agonists: a computational approach for NASH therapy.

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome, posing risks to cardiovascular and hepatic health worldwide. Non-alcoholic steatohepatitis (NASH) which is a severe form of NAFLD, has a global prevalence. Therapeutic targets for NASH include THR-β, GLP-1 receptor, PPARα/δ/γ, FGF21 analogs, and FXR, a bile acid nuclear receptor pivotal for regulating bile acid synthesis and excretion. Our study aims to design the non-steroidal FXR agonist for NASH treatment, as FXR's role in the regulation of bile acid processes, rendering it a promising drug target for NASH therapy. Utilizing tropifexor as a reference molecule, we generated a shape-based pharmacophore model with seven features, identifying key binding requirements within the FXR active site. Virtual screening using this model, coupled with molecular docking studies, helped pinpoint potential ligands from diverse small molecule databases. Further analysis via MM/GBSA revealed 12 molecules with binding affinities comparable to tropifexor. Among them, DB15416 exhibited the lowest binding free energy and superior docking scores. To assess its dynamic stability, we subjected DB15416 to molecular dynamics simulations, confirming its suitability as a FXR agonist. These findings suggest that DB15416 holds promise as a FXR agonist for NASH treatment, which can be evaluated by experimental studies.