In Silico Screening of Helianthus tuberosus L. Phytochemicals as Candidate 5-HT3A Receptor Ligands for Irritable Bowel Syndrome: Molecular Docking, Conformational Flexibility, and ADME/Toxicity Profiling

Dysregulated serotonergic signaling, including altered 5-HT₃ receptor activity, contributes to the pathophysiology of diarrhea-predominant irritable bowel syndrome (IBS-D), yet the most clinically established 5-HT₃A antagonist, alosetron, carries serious safety concerns including ischemic colitis and severe constipation. Helianthus tuberosus L. (Jerusalem artichoke) produces caffeoylquinic acids and flavonoid glycosides with documented gastrointestinal-protective properties, but their potential as direct 5-HT₃A receptor modulators has not been computationally investigated. Here, ten phytochemicals from H. tuberosus L. were evaluated against the orthosteric site of the human 5-HT₃A receptor (PDB: 8AXD) using AutoDock Vina molecular docking, hydrogen bond interaction analysis, CABS-flex 3.0 flexibility profiling, and in silico ADME/toxicity prediction (SwissADME, ProTox 3.0). Nine of ten compounds produced more negative docking scores than alosetron (−7.693 kcal/mol) under the applied conditions; 3,4-dicaffeoylquinic acid (3,4-DiCQA) scored the most negative (−9.151 kcal/mol) and formed five hydrogen bonds at the inter-subunit orthosteric interface (principal chain A: GLY101, SER103, LYS121, GLN124; complementary chain D: ASN105), consistent with the bis-caffeoyl ester scaffold favoring this region. CABS-flex 3.0 analysis (chain A) indicated that the core orthosteric residues (LYS121, GLN124, ARG191, LYS205) remained rigid (RMSF < 1 Å) in the apo receptor and in all complexes, whereas the peripheral GLY101/SER103 segment showed high intrinsic flexibility independent of ligand binding. ProTox 3.0 assigned the phytochemicals to predicted acute-toxicity Class 5 and alosetron to Class 4; these predictions require experimental validation. To our knowledge, this study provides an initial systematic computational assessment identifying selected DiCQA compounds, particularly 3,4-DiCQA, as priority candidates for experimental validation at the 5-HT₃A receptor.