Phytochemical Characterization and Neuropharmacological Assessment of Combretum indicum Methanolic Extract With Integrated Molecular Docking and Dynamics Simulation for Anxiety and Depression Therapy

ABSTRACT A study of the phytochemical composition, as well as in vitro and in vivo neuropharmacological activities of methanol extract of C. indicum ( MECI ) was carried out along with an in silico prediction. GC–MS/MS and FTIR results showed that the PEs contained various bioactive components like flavonoids, terpenoids, alkaloids, heterocyclic substances. In mice, MECI (200 and 400 mg/kg, i.p.) caused significant dose‐dependent anxiolytic effects as indicated by the elevated plus maze test (increased duration and entries in open arms; 166.6 ± 14.71 s, *** p < 0.001), hole‐board test (enhanced head‐dipping frequency; 53.4 ± 4.71; *** p < 0.001), light/dark box test (greatest latency time without suppression of locomotion). Antidepressant‐like effect was evidenced by decreased immobility in forced swim (48.5%–55.1% reduction) and tail suspension test (83.0 ± 2.60 to 72.4 ± 2.33 s), being at the level of efficacy of fluoxetine (67.4 ± 2.87 s). The extract did not have a sedative effect as measured by the open matter and hole‐cross tests. ADME profiling suggested well oral absorption and BBB permeability and PASS prediction indicated possible neuropharmacological activity. Molecular docking revealed that the major constituents (methyl 10,13‐dimethyltetradecanoate; −8.5 kcal/mol) and tetrazolo[1,5‐b]pyridazine (−8.1 kcal/mol) showed strong binding scores with CNS targets as compared to reference drugs. Molecular dynamics simulation revealed that Tetrazolo[1,5‐b]pyridazine forms a structurally stable complex with the 2Z5X protein, supporting its potential anxiolytic activity through favorable conformational stabilization. Toxicity predictions suggested low hepatotoxicity and cardiotoxicity. These results in turn offer mechanistic explanation for ethnomedicinal use of C. indicum to manage anxiety and depression and thus endorse it as a multi‐target natural therapeutic agent against the two mood disorders.