Therapeutic Potential of Natural Compounds from Terminalia chebula in Managing Chronic Constipation: Insights from In Silico Studies Targeting the 5-HT4 Receptor

Introduction: Natural products are increasingly recognized in drug discovery for their diverse pharmacological properties and favorable safety profiles. Terminalia chebula exhibits a range of biological activities, including gastrointestinal benefits. Chronic constipation, a significant clinical challenge often linked to dysregulated serotonergic signaling, targets the serotonin 4 (5-HT4) receptor for intestinal motility modulation. This study investigated the phytochemicals of Terminalia chebula as potential modulators of the 5-HT4 receptor using integrated computational methodologies. Methods: Thirty phytochemicals were virtually screened against the 5-HT4 receptor (PDB ID: 7XT8) using Extra-Precision (XP) docking protocols. The top-scoring compounds were further analyzed via MM-GBSA for binding free energy estimation. The best-performing ligand (TC24) underwent 100 ns Molecular Dynamics (MD) simulations to evaluate the structural stability of the receptor-ligand complex. Pharmacokinetic profiles were assessed through Lipinski’s rule-offive and ADME analysis. Results: TC24 exhibited a high binding affinity (-206.58 kcal/mol) and stable interaction with key catalytic residues (THR96, PHE185). MD simulations confirmed complex stability, with minimal RMSD and RMSF deviations. The compound also fulfilled drug-likeness criteria, indicating potential for favorable oral bioavailability. Discussion: This study integrates traditional herbal medicine with modern computational techniques, highlighting the therapeutic potential of natural compounds. Our findings suggest TC24 from Terminalia chebula can pharmacologically modulate the 5-HT4 receptor, potentially alleviating chronic constipation by restoring intestinal motility. These computational results provide a robust foundation for subsequent in vitro and in vivo studies aimed at developing safe, plantbased therapies for gastrointestinal disorders. This study is solely computational; further experimental validation is essential. Conclusion: TC24 from Terminalia chebula demonstrates promising pharmacological potential as a 5-HT4 receptor modulator. Its targeted interaction may restore intestinal motility in chronic constipation and possibly benefit other hypomotility disorders. These computational findings provide a basis for subsequent in vitro and in vivo studies aimed at developing safe, plant-based therapies for gastrointestinal disorders.