@article {2593, title = {Molecular Docking of Glycyrrhiza glabra Metabolites at TLR4 and MLCK: Non Classical Depression Related Targets in the Gut{\textendash}Brain Axis}, journal = {Pharmacognosy Journal}, volume = {18}, year = {2026}, month = {January 2026}, pages = {74-81}, type = {Original Article}, chapter = {74}, abstract = {

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{\textendash}brain-axis targets relevant to depression remains unclear. Methods: This in silico study investigated the anxiolytic{\textendash}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 ({\textendash}10.2 to {\textendash}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{\textendash}brain-axis-oriented hypothesis. These conclusions are preliminary and require confirmation through targeted in vitro and in vivo studies of efficacy, pharmacokinetics and safety.

}, keywords = {In silico ADMET prediction, Licorice root phytochemicals, Neuroinflammation, Pattern recognition receptors, Stress-related mood disorders}, doi = {10.5530/pj.2026.18.119}, author = {Rajendran Mala and Rajamohan Harseni} }