Author(s):
Raharjo SJ, Sari DRT, Wijayanti ED, Maryanty Y
Email(s):
sentotjoko@poltekkespim.ac.id
DOI:
10.52711/0974-360X.2026.00473 
Address:
Raharjo SJ1*, Sari DRT2, Wijayanti ED3, Maryanty Y4:
1Department of Pharmacy Analyst and Food, Health Polytechnique of Putra Indonesia Malang, Indonesia.
2Department of Pharmacy, Faculty of Health Science, Ibrahimy University, Situbondo, Indonesia.
3Department of Pharmacy, Health of Polytechnique of Putra Indonesia Malang, Indonesia.
4Department of Chemical Engineering, State Polytechnic of Malang, Indonesia.
*Corresponding Author
Published In:
Volume - 19,
Issue - 7,
Year - 2026
ABSTRACT:
Insomnia is the second most prevalent mental disorder and is associated with various health risks. Ginger (Zingiber officinale) essential oil is widely recognized for its diverse therapeutic properties. This study aimed to explore the potential of compounds derived from ginger essential oil as therapeutic agents for insomnia by targeting orexin-1 (OX1R) and orexin-2 (OX2R) receptors through molecular docking and molecular dynamics simulations. Forty compounds identified from ginger essential oil via GC-MS analysis were retrieved from the PubChem database, while the crystal structures of OX1R (PDB ID: 4zj8) and OX2R (PDB ID: 7xrr) were obtained from the Protein Data Bank. These compounds were docked to the active sites of both orexin receptors, and their binding interactions were compared with those of native ligands. Molecular dynamics simulations were performed using OpenMM on Google Colab to assess the binding stability of the compounds using ligands with the best binding affinity. Docking results showed that ginger essential oil compounds bind to the same sites as native ligands on both receptors, exhibiting relatively higher binding affinity and selectivity to OX2R, with alpha-zingiberene identified as the best ligand. MMGBSA and MMPBSA binding energy calculations from molecular dynamics simulations showed ?G values of -8.9200 ± 2.3693 kcal/mol and 0.0226 ± 3.1674 kcal/mol for the alpha-zingiberene–OX2R complex, respectively. In conclusion, molecular docking showed that ginger essential oil compounds generally exhibit selectivity for OX2R. Molecular dynamics simulations also showed that alpha-zingiberene forms a stronger and more stable interaction with OX2R.
Cite this article:
Raharjo SJ, Sari DRT, Wijayanti ED, Maryanty Y. Exploring Zingiber officinale Essential Oils Compounds as Selective Inhibitors of Orexin Receptors: A Comprehensive Molecular Docking and Dynamics Study. Research Journal of Pharmacy and Technology. 2026;19(7):3325-2. doi: 10.52711/0974-360X.2026.00473
Cite(Electronic):
Raharjo SJ, Sari DRT, Wijayanti ED, Maryanty Y. Exploring Zingiber officinale Essential Oils Compounds as Selective Inhibitors of Orexin Receptors: A Comprehensive Molecular Docking and Dynamics Study. Research Journal of Pharmacy and Technology. 2026;19(7):3325-2. doi: 10.52711/0974-360X.2026.00473 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2026-19-7-60
REFERENCES:
1. Burnett A, DiTunnariello N, DeGreeff BL. “I’m on a Rollercoaster”: Women’s Social Construction of Time. Communication Studies. 2020; 71: 148–66. https://doi.org/ 10.1080/10510974.2019.1702073.
2. Lippke S, Schalk TM, Kühnen U, Shang B. Pace of life and perceived stress in international students. PsyCh Journal. 2021; 10: 425–36. https://doi.org/10.1002/pchj.426.
3. Maanickha Chelvi KS, Karthik Nagarajan S, Kanagarajan A. Insomnia Management Clinical Trials by various Conventional Therapies – A Review. Research Journal of Pharmacy and Technology. 2023; 16(12): 6071-6076. https://doi.org/ 10.52711/0974-360X.2023.00985
4. Suneesh PM, Thangavel K, Doss KJJ. A Study to Assess the Effectiveness of Warm Foot Bath on Sleep Onset Time among Cancer Patients with Insomnia in Nath Lal Parekh Cancer Hospital at Rajkot. Asian J Nurs Educ Res. 2017; 7(2): 231-234. https://doi.org/10.5958/2349-2996.2017.00048.9.
5. Sharma M, Prakash K, Priya J. Effectiveness of “Warm Footbath” on fatigue and insomnia in patients undergoing radiotherapy. Int J Nurs Educ Res. 2016; 3(4): 363-366. https://10.5958/2454-2660.2016.00064.8
6. Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F. Orexin System: The Key for a Healthy Life. Front Physiol. 2017; 8: 357. https://doi.org/10.3389/fphys.2017.00357.
7. Wang C, Wang Q, Ji B, Pan Y, Xu C, Cheng B, et al. The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. Front Mol Neurosci. 2018; 11: 220. https://doi.org/10.3389/fnmol.2018.00220.
8. Khazaie H, Sadeghi M, Khazaie S, Hirshkowitz M, Sharafkhaneh A. Dual orexin receptor antagonists for treatment of insomnia: A systematic review and meta-analysis on randomized, double-blind, placebo-controlled trials of suvorexant and lemborexant. Front Psychiatry. 2022; 13: 1070522. https://doi.org/10.3389/fpsyt.2022.1070522.
9. Muehlan C, Roch C, Vaillant C, Dingemanse J. The orexin story and orexin receptor antagonists for the treatment of insomnia. Journal of Sleep Research. 2023; 32: e13902. https://doi.org/10.1111/jsr.13902.
10. Rashmi KS, Maynnavar SK, Arunkumar N, Bhagyalakshmi K, Poojary D, Kadur K, et al. The regulatory role of neurotransmitters in orexin B induced nucleus accumbens dependent alcohol ingestion in wistar albino rats. Res J Pharm Technol. 2020; (13)12: 6224-6230. https://doi.org/ 10.5958/0974-360X.2020.01085.9.
11. Ardianto C, Judoko AL, Aprilia M, Ratri DMN, Ariyani T, Rahmadi M, et al. Effect of Andrographolide and Resveratrol on OX1R and Prepro-orexin mRNA expression in CIPN-induced hypothalamus of mice with oxaliplatin. Res J Pharm Technol. 2022; 15(10): 4765-4771. https://doi.org/ 10.52711/0974-360X.2022.00800
12. Mogavero MP, Silvani A, Lanza G, DelRosso LM, Ferini-Strambi L, Ferri R. Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations. NSS. 2023; 15: 17–38. https://doi.org/10.2147/NSS.S201994.
13. Jasim RF, Allwsh TA. Orexin a hormone and its relation to coronary heart diseases. Res J Pharm Technol. 2021; 14(3): 1417-1422. https://doi.org/10.5958/0974-360X.2021.00253.5.
14. Ajayi BO, Olajide TA, Olayinka ET. 6-gingerol attenuates pulmonary inflammation and oxidative stress in mice model of house dust mite-induced asthma. Advances in Redox Research. 2022; 5: 100036. https://doi.org/10.1016/j.arres.2022.100036.
15. Arcusa R, Villaño D, Marhuenda J, Cano M, Cerdà B, Zafrilla P. Potential Role of Ginger (Zingiber officinale Roscoe) in the Prevention of Neurodegenerative Diseases. Front Nutr. 2022; 9: 809621. https://doi.org/10.3389/fnut.2022.809621.
16. Bare Y, Maulidi A, Sari DRT, Tiring SSND. Studi in Silico Prediksi Potensi 6-Gingerol sebagai inhibitor c-Jun N-terminal kinases (JNK). JJMS. 2019; 1: 59–63. https://doi.org/10.36873/jjms.v1i2.211.
17. Gawel K, Kukula-Koch W, Banono NS, Nieoczym D, Targowska-Duda KM, Czernicka L, et al. 6-Gingerol, a Major Constituent of Zingiber officinale Rhizoma, Exerts Anticonvulsant Activity in the Pentylenetetrazole-Induced Seizure Model in Larval Zebrafish. IJMS. 2021; 22: 7745. https://doi.org/10.3390/ijms22147745.
18. Simon A, Darcsi A, Kéry Á, Riethmüller E. Blood-brain barrier permeability study of ginger constituents. Journal of Pharmaceutical and Biomedical Analysis. 2020; 177: 112820. https://doi.org/10.1016/j.jpba.2019.112820.
19. Wilson SA, Nagaraj A, Vaidyanathan L. Calocybe indicia extract modifies gaba and serotonin levels to alleviate anxiety in experimental adult zebrafish models. Res J Pharm Technol. 2021; 14(9): 4789-4794. https://doi.org/ 10.52711/0974-360X.2021.00833
20. Sawhney SK, Narayan C, Mishra A, Singh M, Kaur A. Molecular Docking, ADME and Toxicity Study of Dibenzo-α-pyrone derivatives for GABA and NMDA receptors for their antiepileptic activity. Res J Pharm Technol. 2024; 17(1): 340-346. https://doi.org/ 10.52711/0974-360X.2024.00053
21. Uddin J, Ahmed H, Asiri YI, Kamal GM, Musharraf SG. Ginger essential oil: Chemical composition, extraction, characterization, pharmacological activities, and applications. Essential Oils, Elsevier. 2023; 345–76. https://doi.org/10.1016/B978-0-323-91740-7.00014-1.
22. Hellmann J, Drabek M, Yin J, Gunera J, Pröll T, Kraus F, et al. Structure-based development of a subtype-selective orexin 1 receptor antagonist. Proc Natl Acad Sci USA. 2020; 117(30): 18059-18067. https//doi.org/ 10.1073/pnas.2002704117.
23. Asada H, Im D, Hotta Y, Yasuda S, Murata T, Suno R, et al. Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor. Structure. 2022; 30: 1582-1589.e4. https://doi.org/10.1016/j.str.2022.11.001.
24. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31: 455–61. https://doi.org/10.1002/jcc.21334.
25. Liao A, Li L, Wang T, Lu A, Wang Z, Wang Q. Erratum: Discovery of Phytoalexin Camalexin and Its Derivatives as Novel Antiviral and Antiphytopathogenic-Fungus Agents. J. Agric. Food Chem. 2022; 70: 2554-2563. https://doi.org/10.1021/acs.jafc.1c07805).
26. Sari D, Safitri A, Cairns J, Fatchiyah F. Virtual screening of black rice anthocyanins as antiobesity through inhibiting TLR4 and JNK pathway. J Phys: Conf Ser. 2020; 1665: 012024. https://doi.org/10.1088/1742-6596/1665/1/012024.
27. Raharjo SJ, Kikuchi T. Molecular dynamic screening sesquiterpenoid pogostemon herba as suggested cyclooxygenase inhibitor. Acta Inform Medica. 2016; 24(5): 332–7. https://doi.org/ 10.5455/aim.2016.24.332-337.
28. Ananda AN, Triawanti T, Setiawan B, Makati AC, Putri JA, Raharjo SJ. In silico study of the flavonoid compound of Sauropus androgynus leaves ON RNA-Dependent RNA polymerase (RdRp) SARS-CoV-2. Asp Mol Med. 2024; 3(6); 1-8. https://doi.org/10.1016/j.amolm.2023.100032
29. Utami PD, Setianingsih H, Sari DRT. In Silico Approach Triterpene Glycoside of H. atra Targeting Orotidine 5-Monophosphate Decarboxylase Protein (PfOMPDC) in P. falciparum Infection Mechanism. BioMed Research International 2024; 2024: 1–14. https://doi.org/10.1155/2024/5924799.
30. Dodda LS, Vilseck JZ, Tirado-Rives J, Jorgensen WL. 1.14*CM1A-LBCC: Localized Bond-Charge Corrected CM1A Charges for Condensed-Phase Simulations. J Phys Chem B. 2017; 12(15): 3864–70.https//doi.org/10.1021/acs.jpcb.7b00272.
31. Dodda LS, Cabeza de Vaca I, Tirado-Rives J, Jorgensen WL. LigParGen web server: an automatic OPLS-AA parameter generator for organic ligands. Nucleic Acids Research. 2017; 45: W331–6. https://doi.org/10.1093/nar/gkx312.
32. Jorgensen WL, Tirado-Rives J. Potential energy functions for atomic-level simulations of water and organic and biomolecular systems. Proc Natl Acad Sci. 2005; 102: 6665–70.
33. Arantes PR, Polêto MD, Pedebos C, Ligabue-Braun R. Making it Rain: Cloud-Based Molecular Simulations for Everyone. J Chem Inf Model. 2021; 61: 4852–6. https://doi.org/10.1021/acs.jcim.1c00998.
34. Cao M, Chow M. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. NSS. 2016: 81. https://doi.org/10.2147/NSS.S76711.
35. Yamanaka M, Iwata H, Masuda K, Araki M, Okuno Y, Okamura M, et al. A novel orexin antagonist from a natural plant was discovered using zebrafish behavioural analysis. European Review for Medical and Pharmacological Sciences 2020; 24: 5127–39. https://doi.org/ 10.26355/eurrev_202005_21207.
36. Reddy PPK, Hiremath JS, Nyamagoud SB, Swamy AHV. A comprehensive review of the use of lemborexant in treating insomnia. MGMJ. 2024; 11: 146–51. https://doi.org/10.4103/mgmj.mgmj_286_23.
37. Krisnamurti GC, Fatchiyah F. The Biological Function Prediction of The 10-gingerol Compound of Ginger in Inhibiting Cyclooxygenase-2 Activity. J Pure App Chem. Res. 2020; 9: 222–32. https://doi.org/10.21776/ub.jpacr.2020.009.03.547.
38. Genheden S and Ryde U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov. 2015; 10(5): 449–461. doi: 10.1517/17460441.2015.1032936
39. Sharma R, Kumari N, Ashawat M., Verma CP. Standardization and phytochemical screening analysis for herbal extracts: Zingiber officinalis, Rosc., Curcuma longa Linn., Cinnamonum zeylanicum Nees., Piper longum, Linn., Boerhaavia diffussa Linn. Asian J Pharm Technol. 2020; 14(1): 341-346. https://doi.org/ 10.52711/0974-360X.2024.00053
40. Kukula-Koch W, Koch W, Czernicka L, Głowniak K, Asakawa Y, Umeyama A, et al. MAO-A Inhibitory Potential of Terpene Constituents from Ginger Rhizomes. A Bioactivity Guided Fractionation. Molecules. 2018; 23: 1301. https://doi.org/10.3390/molecules23061301.
41. Hosseini A, Mirazi N. Alteration of pentylenetetrazole-induced seizure threshold by chronic administration of ginger (Zingiber officinale) extract in male mice. Pharmaceutical Biology. 2015; 53: 752–7. https://doi.org/10.3109/13880209.2014.942789.
42. Shukla SS, Saraf S, Saraf S. Development and validation of spectrophotometric fingerprint method of 6-gingerol in herbal formulation: Talisadi churna. Res J Pharm Technol. 2012; 5(1): 1391-40.
43. Asma ST, Acaroz U, Imre K, Morar A, Shah SRA, Hussain SZ, et al. Natural Products/ Bioactive Compounds as a Source of Anticancer Drugs. Cancers. 2022; 14: 6203. https://doi.org/10.3390/cancers14246203.