Evaluating ginkgetin from Ginkgo biloba as a novel agent for sleep promotion through molecular docking and in vivostudies

Document Type : Original Article

Authors

1 Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

2 Department of Physiology and Medical Physics, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran

3 Department of Pharmacognosy and Traditional Pharmacy, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran

4 Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

10.22038/ijbms.2025.82718.17878

Abstract

Objective(s): Sleep impacts the well-being and quality of life of millions. Given conventional pharmacotherapy’s limitations and side effects, the quest for adequate and proper sleep promotion is imperative. This study aims to identify a suitable and effective compound for sleep by examining qualified herbal compounds in the PubChem database using in silico methods. Ultimately, the extracted compound (ginkgetin, a bioactive flavonoid from Ginkgo biloba) through molecular docking by considering the GABA A receptors will be evaluated through the in vivo method in an animal model to serve as proof for the findings from the molecular docking process.
Materials and Methods: Utilizing a comprehensive approach, this research employed molecular docking to screen 2299 phytochemicals for their affinity towards the GABAA receptor, focusing on the GABA, benzodiazepine, and steroid-binding sites. Ginkgetin emerged as a top candidate due to its high binding affinity. Subsequent in vivo electrophysiological assessments in rats treated with G. biloba extract containing ginkgetin evaluated alterations in sleep architecture, REM, and NREM sleep phases.
Results: Molecular docking identified ginkgetin as possessing the highest binding affinity among the screened phytochemicals. In vivo studies corroborated these findings, demonstrating that rats treated with Ginkgo biloba extract significantly enhanced REM and NREM sleep compared to controls.
Conclusion: Ginkgetin, derived from G. biloba, shows promising potential as a novel therapeutic agent for sleep disorders, supported by its strong affinity to key receptor sites and its efficacy in modulating sleep architecture in vivo. These findings contribute to the expanding evidence base for the therapeutic use of G. biloba in sleep promotion and underscore the need for further research to elucidate the mechanisms and clinical applicability of ginkgetin in sleep disorder treatment.

Keywords

Main Subjects

References

1. Wu C, Sun D. GABA receptors in brain development, function, and injury. Metab Brain Dis 2015;30:367-379.
2. Ghit A, Assal D, Al-Shami AS, Hussein DEE. GABA(A) receptors: Structure, function, pharmacology, and related disorders. J Genet Eng Biotechnol 2021;19:123-138.
3. Simeone TA, Donevan SD, Rho JM. Molecular biology and ontogeny of gamma-aminobutyric acid (GABA) receptors in the mammalian central nervous system. J Child Neurol 2003;18:39–48.
4. Ferranti AS, Luessen DJ, Niswender CM. Novel pharmacological targets for GABAergic dysfunction in ADHD. Neuropharmacology 2024:109897-109915.
5. Koche D, Shirsat R, Kawale M. An overerview of major classes of phytochemicals: their types and role in disease prevention. Hislopia J 2016;9:1-11.
6. Schramm A, Ebrahimi SN, Raith M, Zaugg J, Rueda DC, Hering S, et al. Phytochemical profiling of Curcuma kwangsiensis rhizome extract, and identification of labdane diterpenoids as positive GABAA receptor modulators. Phytochemistry 2013; 96:318-329.
7. Ayaz M, Nawaz A, Naz F, Ullah F, Sadiq A, Islam ZU. Phytochemicals-based therapeutics against Alzheimer’s disease: An update. Curr Top Med Chem  2022; 22:1811-1820.
8. Wang F, Xu Z, Ren L, Tsang SY, Xue H. GABAA receptor subtype selectivity underlying selective anxiolytic effect of baicalin. Neuropharmacology 2008; 55:1231-1237.
9. Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2011;16:383-406.
10. Jakhar R, Dangi M, Khichi A, Chhillar AK. Relevance of molecular docking studies in drug designing. Curr Bioinformatics 2020;15:270-278.
11. Paggi JM, Pandit A, Dror RO. The art and science of molecular docking. Annu Rev Biochem 2024; 93:389-410
12. Kanehisa M, editor The KEGG database. ‘In silico’simulation of biological processes: Novartis Foundation Symposium 247; 2002: Wiley Online Library.
13. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23:3-25.
14. Gimenez B, Santos M, Ferrarini M, Fernandes J. Evaluation of blockbuster drugs under the rule-of-five. Pharmazie 2010; 65:148-152.
15. Morris G, Huey R, Olson A. Using AutoDock for ligand-receptor docking. Curr Protoc Bioinformatics 2008 Dec:Chapter 8:Unit 8.14.
16. 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; 31:455-461.
17. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30:2785-91.
18. Wang WY, Qu HB, Gong XC. [Research progress on percolation extraction process of traditional Chinese medicines]. Zhongguo Zhong Yao Za Zhi. 2020;45:1039-1046.
19. Zhang Q-W, Lin L-G, Ye W-C. Techniques for extraction and isolation of natural products: A comprehensive review. Chin Med 2018;13:1-26.
20. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. BMJ 2006; 332:385-393.
21. Bradley P. British Herbal Compendium. Volume 2: A Handbook of Scientific Information of Widely Used Plant Drugs. British Herbal Compendium Volume 2: A Handbook of Scientific Information of Widely Used Plant Drugs. 2006.
22. Soltani A, Bahrami F, Bahari Z, Shankayi Z, Graily-Afra M, Sahraei H. The effects of Valerian on sleep spindles in a model of neuropathic pain. Sleep Sci 2021;14:133-139.
23.    Tammadon MR, Nobahar M, Hydarinia-Naieni Z, Ebrahimian A, Ghorbani R, Vafaei AA. The effects of valerian on sleep quality, depression, and state anxiety in hemodialysis patients: a randomized, double-blind, crossover clinical trial. Oman Med J 2021;36:e255-264.
24. Tankam JM, Ito M. Inhalation of the essential oil of Piper guineense from Cameroon shows sedative and anxiolytic-like effects in mice. Biol Pharm Bull 2013;36:1608-1614.
25. Lin P-C, Lee P-H, Tseng S-J, Lin Y-M, Chen S-R, Hou W-H. Effects of aromatherapy on sleep quality: A systematic review and meta-analysis. Complement Ther Med 2019;45:156-166.
26. Bagabir S, Ibrahim NK, Bagabir H, Ateeq R. Covid-19 and artificial intelligence: Genome sequencing, drug development and vaccine discovery. J Infect Public Health 2022 ;15:289-296. 
27. Lou J-S, Zhao L-P, Huang Z-H, Chen X-Y, Xu J-T, Tai WC-S, et al. Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine 2021;80:153370-153431.
28. Adnan M, Rasul A, Hussain G, Shah MA, Zahoor MK, Anwar H, et al. Ginkgetin: A natural biflavone with versatile pharmacological activities. Food Chem Toxicol 2020;145:111642-111656.
29.    Tang T, Wang X, Qi E, Li S, Sun H. Ginkgetin promotes M2 polarization of microglia and exert neuroprotection in ischemic stroke via modulation of PPARγ pathway. Neurochem Res 2022; 47:2963-2974.
30. Tian Z, Tang C, Wang Z. Neuroprotective effect of ginkgetin in experimental cerebral ischemia/reperfusion via apoptosis inhibition and PI3K/Akt/mTOR signaling pathway activation. J Cell Biochem 2019;120:18487-18495.
31. Wang Y-Q, Wang M-Y, Fu X-R, Peng-Yu, Gao G-F, Fan Y-M, et al. Neuroprotective effects of ginkgetin against neuroinjury in Parkinson’s disease model induced by MPTP via chelating iron. Free Radic Res 2015; 49:1069-1080.
32. Tao Z, Bai S, Wu G, Zhai S, Zhang P, Fu C, et al. Therapeutic effect of ginkgetin on smoke-induced airway inflammation by down-regulating the C/Ebpβ signaling pathway and Ccl2 expression. J Ethnopharmacol 2024;331:118284.
33. Tatlı Çankaya İİ, Devkota HP, Zengin G, Šamec D. Neuroprotective potential of biflavone ginkgetin: A review. Life 2023;13:562-577.
34. Zhang L, Li G, Bao Y, Liu M. Role of sleep disorders in patients with cardiovascular disease: A systematic review. Int J Cardiol Cardiovasc Risk Prev 2024:200257-200278.
35. Dey S, Sun E, Frishman WH, Aronow WS. Sleep disorders and coronary artery disease. Cardiol Rev 2023; 31:219-224.
36. Duan D, Jun JC. Obesity, Metabolic Syndrome, and Sleep Disorders.  Metabolic Syndrome: A Comprehensive Textbook: Springer; 2024. p. 639-658.
37. Streatfeild J, Smith J, Mansfield D, Pezzullo L, Hillman D. The social and economic cost of sleep disorders. Sleep 2021; 44:zsab132.
38. Kramer DJ, Johnson AA. Apigenin: A natural molecule at the intersection of sleep and aging. Front Nutr 2024;11:1359176.
39. Dai X, Xie L, Liu K, Liang Y, Cao Y, Lu J, et al. The neuropharmacological effects of magnolol and honokiol: A review of signal pathways and molecular mechanisms. Curr Mol Pharmacol 2023;16:161-177.
40.    Chen C-R, Zhou X-Z, Luo Y-J, Huang Z-L, Urade Y, Qu W-M. Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABAA receptor in mice. Neuropharmacology 2012; 63:1191-1199.
41. Abdul‐Rahman T, Awuah WA, Mikhailova T, Kalmanovich J, Mehta A, Ng JC, et al. Anti-oxidant, anti‐inflammatory and epigenetic potential of curcumin in Alzheimer’s disease. BioFactors 2024; 50:693-708.
42. Zhang S, Kiarasi F. Therapeutic effects of resveratrol on epigenetic mechanisms in age‐related diseases: A comprehensive review. Phytother Res 2024; 38:2347-2360.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 6
June 2025
Pages 746-754

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