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

Gamze Altıntaş Kazar

doi:10.28979/jarnas.1942434

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

Abstract

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.

Keywords

Ethical Statement

No approval from the Board of Ethics is required.

References

R. M. Lovell, A. C. Ford, Global prevalence of and risk factors for irritable bowel syndrome: A meta-analysis, Clinical Gastroenterology and Hepatology 10 (7) (2012) 712–721.e4.
B. E. Lacy, F. Mearin, L. Chang, W. D. Chey, A. J. Lembo, M. Simren, R. Spiller, Bowel disorders, Gastroenterology 150 (6) (2016) 1393–1407.e5.
C. Canavan, J. West, T. Card, The epidemiology of irritable bowel syndrome, Clinical Epidemiology 6 (2014) 71–80.
M. D. Crowell, Role of serotonin in the pathophysiology of the irritable bowel syndrome, British Journal of Pharmacology 141 (8) (2004) 1285–1293.
S. Kato, Role of serotonin 5-HT3 receptors in intestinal inflammation, Biological and Pharmaceutical Bulletin 36 (9) (2013) 1406–1409.
B. Niesler, 5-HT3 receptors: Potential of individual isoforms for personalised therapy, Current Opinion in Pharmacology 11 (1) (2011) 81–86.
A. J. Thompson, S. C. R. Lummis, Discriminating between 5-HT3A and 5-HT3AB receptors, British Journal of Pharmacology 169 (4) (2013) 736–747.
R. C. Spiller, Targeting the 5-HT3 receptor in the treatment of irritable bowel syndrome, Current Opinion in Pharmacology 11 (1) (2011) 68–74.

D.-C. Jin, H.-L. Cao, M.-Q. Xu, S.-N. Wang, Y.-M. Wang, F. Yan, B.-M. Wang, Regulation of the serotonin transporter in the pathogenesis of irritable bowel syndrome, World Journal of Gastroenterology 22 (36) (2016) 8137–8148.
B. Greenwood-Van Meerveld, Importance of 5-hydroxytryptamine receptors on intestinal afferents in the regulation of visceral sensitivity, Neurogastroenterology and Motility 19 (Suppl. 2) (2007) 13–18.
A. Y. Thijssen, Z. Mujagic, D. M. A. E. Jonkers, S. Ludidi, D. Keszthelyi, M. A. Hesselink, C. H. M. Clemens, J. M. Conchillo, J. W. Kruimel, A. A. M. Masclee, Alterations in serotonin metabolism in the irritable bowel syndrome, Alimentary Pharmacology & Therapeutics 43 (2) (2016) 272–282.
Y. Zheng, T. Yu, Y. Tang, W. Xiong, X. Shen, L. Jiang, L. Lin, Efficacy and safety of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: A systematic review and meta-analysis of randomized controlled trials, PLOS One 12 (3) (2017) e0172846.
Y. W. Min, P. L. Rhee, The clinical potential of ramosetron in the treatment of irritable bowel syndrome with diarrhea (IBS-D), Therapeutic Advances in Gastroenterology 8 (3) (2015) 136–142.
D. Gunn, R. Topan, R. Fried, I. Holloway, R. Brindle, S. Hartley, L. Barnard, M. Corsetti, S. M. Scott, …, R. Spiller, Ondansetron for irritable bowel syndrome with diarrhoea: Randomised controlled trial, Efficacy and Mechanism Evaluation 10 (9) (2023) 1–121.
T. Rokkas, K. Ekmektzoglou, Y. Niv, Comparative effectiveness of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: A network meta-analysis of randomized controlled studies, Annals of Gastroenterology 34 (4) (2021) 535–546.
S. Basak, Y. Gicheru, A. Samanta, S. K. Molugu, W. Huang, M. L. De Fuente, T. Hughes, D. J. Taylor, M. T. Nieman, V. Moiseenkova-Bell, S. Chakrapani, Cryo-EM structure of 5-HT3A receptor in its resting conformation, Nature Communications 9 (2018) 514.
D. C. Reeves, M. F. R. Sayed, P. L. Chau, K. L. Price, S. C. R. Lummis, Prediction of 5-HT3 receptor agonist-binding residues using homology modeling, Biophysical Journal 84 (4) (2003) 2338–2344.
A. J. Moura Barbosa, F. De Rienzo, M. J. Ramos, M. C. Menziani, Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors, European Journal of Medicinal Chemistry 45 (11) (2010) 4746–4760.
F. Chen, X. Long, Z. Liu, H. Shao, L. Liu, Analysis of phenolic acids of Jerusalem artichoke (Helianthus tuberosus L.) responding to salt-stress by liquid chromatography/tandem mass spectrometry, The Scientific World Journal 2014 (2014) 568043. M. M. Showkat, A. B. Falck-Ytter, K. O. Strætkvern, Phenolic acids in Jerusalem artichoke (Helianthus tuberosus L.): Plant organ dependent antioxidant activity and optimized extraction from leaves, Molecules 24 (18) (2019) 3296.
X. Yuan, M. Gao, H. Xiao, C. Tan, Y. Du, Free radical scavenging activities and bioactive substances of Jerusalem artichoke (Helianthus tuberosus L.) leaves, Food Chemistry 133 (1) (2012) 10–14.
H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourne, The Protein Data Bank, Nucleic Acids Research 28 (1) (2000) 235–242.
U. López-Sánchez, L. J. Munro, L. K. Ladefoged, A. J. Pedersen, C. C. Brun, S. M. Lyngby, D. Baud, C. Juillan-Binard, M. G. Pedersen, …, A. S. Kristensen, Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors, Nature Structural & Molecular Biology 31 (8) (2024) 1232–1242.
S. Kim, J. Chen, T. Cheng, A. Gindulyte, J. He, S. He, Q. Li, B. A. Shoemaker, P. A. Thiessen, …, E. E. Bolton, PubChem 2023 update, Nucleic Acids Research 51 (D1) (2023) D1373–D1380.
E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt, E. C. Meng, T. E. Ferrin, UCSF Chimera — a visualization system for exploratory research and analysis, Journal of Computational Chemistry 25 (13) (2004) 1605–1612.
J. Eberhardt, D. Santos-Martins, A. F. Tillack, S. Forli, AutoDock Vina 1.2.0: New docking methods, expanded force field, and Python bindings, Journal of Chemical Information and Modeling 61 (8) (2021) 3891–3898.
S. Basak, A. Kumar, S. Ramsey, E. Gibbs, A. Kapoor, M. Filizola, S. Chakrapani, High-resolution structures of multiple 5-HT3AR–setron complexes reveal a novel mechanism of competitive inhibition, eLife 9 (2020) e57870. M. Lochner, S. C. R. Lummis, Agonists and antagonists bind to an A–A interface in the heteromeric 5-HT3AB receptor, Biophysical Journal 98 (8) (2010) 1494–1502. K. Wróblewski, M. Zalewski, A. Kuriata, S. Kmiecik, CABS-flex 3.0: An online tool for simulating protein structural flexibility and peptide modeling, Nucleic Acids Research 53 (W1) (2025) W95–W101.
M. Y. Alsedfy, A. A. Ebnalwaled, M. Moustafa, A. H. Said, Investigating the binding affinity, molecular dynamics, and ADMET properties of curcumin-IONPs as a mucoadhesive bioavailable oral treatment for iron deficiency anemia, Scientific Reports 14 (2024) 22027.
A. Daina, O. Michielin, V. Zoete, SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Scientific Reports 7 (2017) 42717.
C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews 46 (1-3) (2001) 3–26.
A. K. Ghose, V. N. Viswanadhan, J. J. Wendoloski, A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases, Journal of Combinatorial Chemistry 1 (1) (1999) 55–68. D. F. Veber, S. R. Johnson, H. Y. Cheng, B. R. Smith, K. W. Ward, K. D. Kopple, Molecular properties that influence the oral bioavailability of drug candidates, Journal of Medicinal Chemistry 45 (12) (2002) 2615–2623. W. J. Egan, K. M. Merz, J. J. Baldwin, Prediction of drug absorption using multivariate statistics, Journal of Medicinal Chemistry 43 (21) (2000) 3867–3877.
I. Muegge, S. L. Heald, D. Brittelli, Simple selection criteria for drug-like chemical matter, Journal of Medicinal Chemistry 44 (12) (2001) 1841–1846.
A. Daina, V. Zoete, A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules, ChemMedChem 11 (11) (2016) 1117–1121.
P. Banerjee, E. Kemmler, M. Dunkel, R. Preissner, ProTox 3.0: A webserver for the prediction of toxicity of chemicals, Nucleic Acids Research 52 (W1) (2024) W513–W520.
O. Trott, A. J. Olson, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, Journal of Computational Chemistry 31 (2) (2010) 455–461. T. E. Tallei, S. G. Tumilaar, N. J. Niode, Fatimawali, B. J. Kepel, R. Idroes, Y. Effendi, S. A. Sakib, T. Bin Emran, Potential of plant bioactive compounds as SARS-CoV-2 main protease (Mpro) and spike (S) glycoprotein inhibitors: A molecular docking study, Scientifica 2020 (2020) 6307457.
S. Jo, S. Kim, D. H. Shin, M. S. Kim, Inhibition of SARS-CoV 3CL protease by flavonoids, Journal of Enzyme Inhibition and Medicinal Chemistry 35 (1) (2020) 145–151.
R. Ghosh, A. Chakraborty, A. Biswas, S. Chowdhuri, Evaluation of green tea polyphenols as novel coronavirus (SARS-CoV-2) main protease (Mpro) inhibitors: An in silico docking and molecular dynamics simulation study, Journal of Biomolecular Structure and Dynamics 39 (12) (2021) 4362–4374.
M. Usta, A. Guller, S. Demirel, G. Korkmaz, Z. Kurt, New insights into tomato spotted wilt orthotospovirus (TSWV) infections in Türkiye: Molecular detection, phylogenetic analysis, and in silico docking study, Notulae Botanicae Horti Agrobotanici Cluj-Napoca 51 (3) (2023) 13245.
B. C. Doak, B. Over, F. Giordanetto, J. Kihlberg, Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates, Chemistry & Biology 21 (9) (2014) 1115–1142.
P. Ramnani, E. Gaudier, M. Bingham, P. Van Bruggen, K. M. Tuohy, G. R. Gibson, Prebiotic effect of fruit and vegetable shots containing Jerusalem artichoke inulin: A human intervention study, British Journal of Nutrition 104 (2) (2010) 233–240.
C. Iraporda, A. Errea, D. E. Romanin, D. Cayet, E. Pereyra, O. Pignataro, J. C. Sirard, G. L. Garrote, A. G. Abraham, M. Rumbo, Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells, Immunobiology 220 (10) (2015) 1161–1169.

Details

Primary Language

English

Subjects

Molecular Docking, Proteomics and Intermolecular Interactions, Natural Products and Bioactive Compounds

Journal Section

Research Article

Authors

Gamze Altıntaş Kazar ^*
0000-0002-0220-0263
Türkiye

Publication Date

September 30, 2026

Submission Date

May 2, 2026

Acceptance Date

September 1, 2026

Published in Issue

Year 2026 Volume: 12 Number: 3

DOI

https://doi.org/10.28979/jarnas.1942434

IZ

https://izlik.org/JA63ZX44KB

Cite

RIS / Bibtex

APA

Altıntaş Kazar, G. (2026). 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. Journal of Advanced Research in Natural and Applied Sciences, 12(3), 249-263. https://doi.org/10.28979/jarnas.1942434

AMA

1.Altıntaş Kazar G. 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. JARNAS. 2026;12(3):249-263. doi:10.28979/jarnas.1942434

Chicago

Altıntaş Kazar, Gamze. 2026. “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”. Journal of Advanced Research in Natural and Applied Sciences 12 (3): 249-63. https://doi.org/10.28979/jarnas.1942434.

EndNote

Altıntaş Kazar G (September 1, 2026) 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. Journal of Advanced Research in Natural and Applied Sciences 12 3 249–263.

IEEE

[1]G. Altıntaş Kazar, “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”, JARNAS, vol. 12, no. 3, pp. 249–263, Sept. 2026, doi: 10.28979/jarnas.1942434.

ISNAD

Altıntaş Kazar, Gamze. “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”. Journal of Advanced Research in Natural and Applied Sciences 12/3 (September 1, 2026): 249-263. https://doi.org/10.28979/jarnas.1942434.

JAMA

1.Altıntaş Kazar G. 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. JARNAS. 2026;12:249–263.

MLA

Altıntaş Kazar, Gamze. “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”. Journal of Advanced Research in Natural and Applied Sciences, vol. 12, no. 3, Sept. 2026, pp. 249-63, doi:10.28979/jarnas.1942434.

Vancouver

1.Gamze Altıntaş Kazar. 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. JARNAS. 2026 Sep. 1;12(3):249-63. doi:10.28979/jarnas.1942434

DOAJ	EBSCO
Scilit	SOBİAD