Molecular Docking of Glycyrrhiza glabra Metabolites at TLR4 and MLCK: Non Classical Depression Related Targets in the Gut–Brain Axis

Introduction: Licorice (Glycyrrhiza glabra L.) is traditionally used for stress, mood and sleep disturbances, but the capacity of its major metabolites to modulate non‑classical gut–brain‑axis targets relevant to depression remains unclear. Methods: This in silico study investigated the anxiolytic–antidepressant potential of nine literature‑reported licorice constituents. These included triterpenoid saponins, triterpenoid acids and prenylated/flavonoid scaffolds. The compounds were docked against two peripheral targets that couple inflammation and barrier dysfunction to mood disorders, namely Toll‑like receptor 4 (TLR4) and myosin light‑chain kinase (MLCK). Molecular docking was performed using CB‑Dock2 with resatorvid (TLR4) and 5-iodonaphthalene-1-sulfonyl homopiperazine (MLCK) as reference antagonists, and drug‑likeness and safety were evaluated by in silico ADMET prediction. Results: Several metabolites, particularly hispaglabridin A, O‑(3‑hydroxy‑6‑oxo‑7‑drimen‑11‑yl)umbelliferone and 3‑oxoglycyrrhetinic acid, showed docking scores at TLR4 (–10.2 to –11.0 kcal/mol) that exceeded resatorvid, and ligands occupied the canonical antagonist pocket, supporting a potential TLR4‑mediated anti‑inflammatory mechanism. At MLCK, glycyrrhizin, licorice saponin and flavonoid rhamnosides formed 5-iodonaphthalene- 1-sulfonyl homopiperazine like complexes in the catalytic groove. ADMET profiling revealed that bulky saponins exhibited high polarity, whereas triterpenoid acids and hispaglabridin A showed high lipophilicity and extensive plasma protein binding. Conclusions: Collectively, these findings suggest that G. glabra metabolites can, in principle, engage TLR4 and MLCK in a complementary manner, outlining a polypharmacological, gut–brain‑axis‑oriented hypothesis. These conclusions are preliminary and require confirmation through targeted in vitro and in vivo studies of efficacy, pharmacokinetics and safety.