Leaf-derived Bioactive Compounds of Elaeocarpus ganitrus as a Natural Antidepressant Agent Through Glycogen Synthase Kinase 3 Beta (GSK3β) and Serotonin 6 (5-HT6) Receptor: In silico Approach
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Abstract
Depression is related to molecular and cellular abnormalities that interact with genetic and environmental factors. This condition was traditionally treated by Rudraksha beads of Elaeocarpus ganitrus, also known as natural tranquillizers. Glycogen Synthase Kinase 3 Beta (GSK3β) and Serotonin 6 receptor (5-HT6) played a significant role in mood regulation through Wnt and Akt signalling pathways, respectively. Therefore, this study aims to identify the antidepressant mechanism of E. ganitrus bioactive compounds through GSK3β and 5-HT6 using molecular docking. Bioactive compounds were virtually predicted for drug-likeness properties, ADME/T, and biological activity with PASS Way2Drug. 4-phenylpiperidine and medifoxamine had potent biological activity related to antidepressant mechanisms (Pa > 0.7) and satisfied the criteria of drug-likeness as Lipinski’s rule of five. These compounds were subjected to molecular docking with GSK3β (1UV5) and 5-HT6 (7XTB) using AutoDock Vina integrated in PyRx 0.8. Furthermore, 4-phenylpiperidine and medifoxamine tended to perform antidepressant activity through GSK3β. These bioactive compounds occupied the same binding site as native ligand BRW on GSK3β, but the binding energy of 4-phenylpiperidine (-7.4 kcal/mol) and medifoxamine (-7 kcal/mol) was lower than BRW (-9.7 kcal/mol). Bioactive compounds were bound to the same site on 5-HT6 as the native ligand SRO. Compared to SRO (-6.5 kcal/mol), 4-phenylpiperidine (-6.3 kcal/mol) exhibited weaker binding, while medifoxamine (-6.7 kcal/mol) was stronger. These results supported the traditional use of Rudraksha beads as antidepressants. However, further studies were essential to validate the therapeutic utility of E. ganitrus.
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1. Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 2012; 35(1):47-56. Doi: 10.1016/j.tins.2011.11.004
2. Jain NK, Tailang M, Chandrasekaran B, Khazaleh NT, Thangavel N, Makeen HA, Albratty M, Najmi A, Alhazmi HA, Zoghebi K, Alagusundaram M, Jain HK. Integrating network pharmacology with molecular docking to rationalize the ethnomedicinal use of Alchornea laxiflora (Benth.) Pax & K. Hoffm. for efficient treatment of depression. Front Pharmacol. 2024; 15:1290398. Doi: 10.3389/fphar.2024.1290398
3. Basrowi RW, Wiguna T, Samah K, Moeloek NDF, Soetrisno M, Purwanto SA, Ekowati M, Elisabeth A, Rahadian A, Ruru B, Pelangi B. Exploring Mental Health Issues and Priorities in Indonesia Through Qualitative Expert Consensus. Clin Pract Epidemiol Ment Health. 2024; 20:e17450179331951. Doi: 10.2174/0117450179331951241022175443
4. Friedrich MJ. Depression is the leading cause of disability around the world. JAMA. 2017; 317(15):1517-1517. Doi: 10.1001/jama.2017.3826
5. Abebe T, Hymete A, Giday M, Bisrat D. Antidepressant‐Like Activity and Molecular Docking Analysis of a Sesquiterpene Lactone Isolated from the Root Bark of Ximenia americana (L.). Evid Based Complement Alternat Med. 2024; 2024(1):6680821. Doi: 10.1155/2024/6680821
6. Marcinkowska M, Mordyl B, Siwek A, Głuch-Lutwin M, Karcz T, Gawalska A, Sapa M, Bucki A, Szafrańska K, Pomierny B, Pytka K, Kotańska M, Mika K, Kolaczkowski M. Dual molecules targeting 5-HT6 and GABA-A receptors as a new approach to combat depression associated with neuroinflammation. ACS Chem Neurosci. 2023;14(8):1474-1489. Doi: 10.1021/acschemneuro.3c00033
7. Ramic E, Prasko S, Gavran L, Spahic E. Assessment of the Antidepressant Side Effects Occurrence in Patients Treated in Primary Care. Mater Sociomed. 2020; 32(2):131–134. Doi: 10.5455/msm.2020.32.131-134
8. Braund TA, Tillman G, Palmer DM, Gordon E, Rush AJ, Harris AW. Antidepressant side effects and their impact on treatment outcome in people with major depressive disorder: an iSPOT-D report. Transl Psychiatry. 2021; 11(1):417. Doi: 10.1038/s41398-021-01533-1
9. Rahman MA, Sarkar KK, Aktaruzzaman M, Mitra T, Sarker MT, Abid MA, Mazumder K, Barman AK, Molla NU, Al Hossain,
AM. Evaluation of antioxidant, anxiolytic, and antidepressant potential of Saurauia roxburghii Wall. Leaves: Supported by in vitro, in vivo, and in silico approaches. Phytomedicine Plus. 2025; 5(2):100792. Doi: 10.1016/j.phyplu.2025.100792
10. Choudhary S, Kaurav H. Elaeocarpus ganitrus (Rudraksha): A drug with spiritual and medicinal properties. Int J Pharm Biol Sci. 2009; 11(3):242-253.
11. Sudradjat SE, Timotius KH. Pharmacological properties and phytochemical components of Elaeocarpus: A comparative study. Phytomedicine Plus. 2022; 2(4):100365. Doi: 10.1016/j.phyplu.2022.100365
12. Primiani CN, Bhagawan WS, Pujiati P, Sari DRT. Phytochemical screening, in vitro and in silico antibacterial investigation of Elaeocarpus ganitrus extract. J.Biota. 2024; 10(1):1-14. Doi: 10.19109/Biota.v10i1.20038
13. Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009;136(6):1017–1031. Doi: 10.1016/j.cell.2008.12.044
14. Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO, Ugwuja EI, Aja PM. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in disease management. Sci Rep. 2023 13(1):13398. Doi: 10.1038/s41598-023-40160-2
15. Khansa NM, Pujiati P, Bhagawan WS, Primiani CN. Phytochemical profile of Genitri (Rudraksha) leaf (Elaeocarpus ganitrus) in the Gunungpati, Semarang area using the UPLC-MS method [Profil fitokimia daun genitri (Elaeocarpus ganitrus) pada daerah Gunungpati Semarang dengan metode UPLC-MS]. In Prosiding Seminar Nasional Program Studi Farmasi UNIPMA (SNAPFARMA). 2023 October; 1(1):192-196.
16. Eva MA, Mia E, Al Hasan MS, Chowdhury R, Yana NT, Rakib IH, Akter SM, Situ SG, Islam MT. Fruit-derived bioactive compounds of Malus domestica as novel therapeutic inhibitors against Monkeypox and Marburg virus: A computational-based drug discovery study. Food Chem. Adv. 2025; 7:100998. Doi: 10.1016/j.focha.2025.100998
17. Zareei S, Pourmand S, Eskandarzadeh M, Massahi S. In silico anti-alzheimer study of phytochemicals from Lamiaceae family through GSK3-β inhibition. Sci Rep. 2024; 14(1): 834. Doi: 10.1038/s41598-023-47069-w
18. Krisnamurti GC, Sari DRT, Bare Y. Capsaicinoids from Capsicum annuum as an Alternative fabh Inhibitor of Mycobacterium tuberculosis: in silico study. Makara J. Sci. 2021; 25(4): 195−202. Doi:10.7454/mss.v25i4.1248
19. Giordano D, Biancaniello C, Argenio MA, Facchiano A. Drug design by pharmacophore and virtual screening approach. Pharmaceuticals. 2022; 15(5): 646. Doi: 10.3390/ph15050646
20. Krisnamurti GC, Fatchiyah F. The biological function prediction of the 10-gingerol compound of ginger in inhibiting cyclooxygenase-2 activity. Doi: J. pure appl. chem. res. 2020; 9(3):222-232. Doi: 10.21776/ub.jpacr.2020.009.03.547
21. Ferdausi N, Islam S, Rimti FH, Quayum ST, Arshad EM, Ibnat A, Islam T, Arefin A, Ema TI, Biswas P, Dey D, Al Azad S. Point-specific interactions of isovitexin with the neighboring amino acid residues of the hACE2 receptor as a targeted therapeutic agent in suppressing the SARS-CoV-2 influx mechanism. J Adv Vet Anim Res. 2022; 9(2): 230-240. Doi: 10.5455/javar.2022.i588
22. Ślifirski G, Król M, Turło J. 5-HT Receptors and the Development of New Antidepressants. Int J Mol Sci. 2021; 22(16):9015. Doi: 10.3390/ijms22169015
23. Ragozzino E, Brancaccio M, Di Costanzo A, Scalabrì F, Andolfi G, Wanderlingh LG, Patriarca EJ, Minchiotti G, Altamura S, Summa V, Varrone, F. 6-Bromoindirubin-3'-oxime intercepts GSK3 signaling to promote and enhance skeletal muscle differentiation affecting miR-206 expression in mice. Sci Rep. 2019; 9(1):18091. Doi: 10.1038/s41598-019-54574-4
24. Marliana E, Danova A, Hairani R, Ruga R, Hermawati E, Yulvia A. In vitro Evaluation and Molecular Docking Study of the Antibacterial Potential of Macaranga hullettii King ex Hook. f. Leaf Extract. Trop. J. Nat. Prod. Res. 2025; 9(7):3050 -3057. Doi: 10.26538/tjnpr/v9i7.15
25. Duda P, Akula SM, Abrams SL, Steelman LS, Martelli AM, Cocco L, Ratti S, Candido S, Libra M, Montalto G, Cervello M, Gizak A, Rakus D, McCubrey JA. Targeting GSK3 and associated signaling pathways involved in cancer. Cells. 2020; 9(5): 1110. Doi: 10.3390/cells9051110
26. Li X, Jope RS. Is glycogen synthase kinase-3 a central modulator in mood regulation?. Neuropsychopharmacology. 2010; 35(11): 2143-2154. Doi: 10.1038/npp.2010.105
27. Wang LL, Li J, Gu X, Wei L, Yu SP. Delayed treatment of 6-Bromoindirubin-3′-oxime stimulates neurogenesis and functional recovery after focal ischemic stroke in mice. Int J Dev Neurosci. 2017; 57: 77-84. Doi: 10.1016/j.ijdevneu.2017.01.002
28. Bebeji MY, Yaro AH. Evaluation of antidepressant activity of ethanol leaf extract of Entada africana Guill. & Perr. (Fabaceae) in mice. Trop. J. Nat. Prod. Res. 2024; 8(2):6446-6450.
29. Welcome MO. Cellular mechanisms and molecular signaling pathways in stress-induced anxiety, depression, and blood–brain barrier inflammation and leakage. Inflammopharmacol. 2020; 28:643–665. Doi: 10.1007/s10787-020-00712-8
30. Cheng Y, Desse S, Martinez A, Worthen RJ, Jope RS, Beurel E. TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice. Brain Behav Immun. 2018; 69:556-567. Doi: 10.1016/j.bbi.2018.02.003.
31. Primiani CN, Sari DR, Krisnamurti GC, Pujiati P, Setiawan MA. Anti-Inflammatory Potentials of Elaeocarpus sphaericus Schum Fruit Compounds by Molecular Docking Approach. Trop. J. Nat. Prod. Res. 2021; 6(10):1775-1781. Doi: doi.org/10.26538/tjnpr/v5i10.13
32. da Silva DMA, Sales ISL, Oliveira JVS, dos Santos Júnior MA, de Oliveira Rebouças M, Valentim JT, de Carvalho Vale L, Capibaribe VCC, de Carvalho MAJ, de Aquino PEA, Macêdo DS, de Sousa FCF. Cyclooxygenase-2 inhibitors alleviated depressive and anxious-like behaviors in mice exposed to lipopolysaccharide: Involvement of oxidative stress and neuroinflammation. Pharmacol. Biochem. Behav. 2024; 240:173778. Doi: 10.1016/j.pbb.2024.173778