In Silico Assessment of GSK-3? Inhibition Activity by Secondary Metabolites of Centella asiatica in the Development of Alzheimer’s Therapy
DOI:
https://doi.org/10.25026/jtpc.v9i2.671Keywords:
Centella asiatica, GSK-3β, Molecular Docking, Alzheimer's Disease, Secondary MetabolitesAbstract
Alzheimer’s disease involves excessive activity of glycogen synthase kinase-3? (GSK-3?), leading to tau hyperphosphorylation and neurofibrillary tangle formation. This study evaluated the potential of secondary metabolites from Centella asiatica as GSK-3? inhibitors using in silico molecular docking. The GSK-3? structure (PDB ID: 1Q5K) and ten test compounds were docked using YASARA-structure, with method validation yielding an RMSD of 1.890 Å. Naringin, luteolin, and betulinic acid demonstrated the strongest binding affinities -9.2670, -8.1520, and -7.9730 kcal/mol, surpassing the native ligand. Naringin and luteolin interacted with key ATP-binding residues (Asp133, Tyr134, Val135, Lys85), indicating strong competitive inhibitory potential. These findings suggest that C. asiatica metabolites, particularly naringin and luteolin, are promising natural candidates for GSK-3? inhibitor Alzheimer’s therapy.
Keywords: Centella asiatica; GSK-3?; Molecular Docking; Alzheimer’s Disease; Secondary Metabolites
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[1] M. B. Abubakar et al., 2022. Alzheimer’s Disease: An Update and Insights Into Pathophysiology, Front Aging Neurosci, vol. 14, p. 742408 DOI: 10.3389/FNAGI.2022.742408.
[2] WHO, 2025. 10 penyebab kematian teratas. [Online]. Available: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
[3] J. R. DiBello et al., 2023. “Patterns of use of symptomatic treatments for Alzheimer’s disease dementia (AD),” BMC Neurology 2023 23:1, vol. 23, no. 1, pp. 1–9. DOI: 10.1186/S12883-023-03447-5.
[4] C. L. Sayas and J. Ávila, 2021. GSK-3 and Tau: A Key Duet in Alzheimer’s Disease, Cells, vol. 10, no. 4, p. 721. DOI: 10.3390/CELLS10040721.
[5] J. H. Park et al., 2017. Anti-Inflammatory Effect of Titrated Extract of Centella asiatica in Phthalic Anhydride-Induced Allergic Dermatitis Animal Model, Int J Mol Sci, vol. 18, no. 4. DOI: 10.3390/IJMS18040738.
[6] Yahya, M. A., & Nurrosyidah, I. H, 2020. Aktivitas antioksidan ekstrak etanol herba pegagan (Centella asiatica (L.) Urban) dengan metode DPPH (2, 2-Difenil-1-Pikrilhidrazil), Journal of Halal Product and Research, 3(2), 106-112.
[7] S. M. Chiroma et al., 2019. Centella asiatica Protects d-Galactose/AlCl3 Mediated Alzheimer’s Disease-Like Rats via PP2A/GSK-3? Signaling Pathway in Their Hippocampus, Int J Mol Sci, vol. 20, no. 8, p. 1871. DOI: 10.3390/IJMS20081871.
[8] N. S. Pagadala, K. Syed, and J. Tuszynski, 2017. Software for molecular docking: a review, Biophys Rev, vol. 9, no. 2, p. 91. DOI: 10.1007/S12551-016-0247-1.
[9] R. Silvia et al., 2024. LC-HRMS-Based Metabolomics Approach Reveals Antioxidant Compounds from Centella asiatica Leaves Extracts, Indonesian Journal of Chemistry, vol. 24, no. 6, pp. 1861–1869. DOI: 10.22146/IJC.90782.
[10] R. Shukla and T. R. Singh, 2021. High-throughput screening of natural compounds and inhibition of a major therapeutic target HsGSK-3? for Alzheimer’s disease using computational approaches, Journal of Genetic Engineering and Biotechnology, vol. 19, no. 1. DOI: 10.1186/s43141-021-00163-w.
[11] Z. Zhao, Y. Yuan, S. Li, X. Wang, and X. Yang, 2024. Natural compounds from herbs and nutraceuticals as glycogen synthase kinase-3? inhibitors in Alzheimer’s disease treatment, CNS Neurosci Ther, vol. 30, no. 8. DOI: 10.1111/CNS.14885.
[12] C. Shao, S. Bittrich, S. Wang, and S. K. Burley, 2022. Assessing PDB macromolecular crystal structure confidence at the individual amino acid residue level, Structure, vol. 30, no. 10, pp. 1385-1394.e3. DOI: 10.1016/J.STR.2022.08.004.
[13] M. K. Mazumder and S. Choudhury, 2019. Tea polyphenols as multi-target therapeutics for Alzheimer’s disease: An in silico study, Med Hypotheses, vol. 125, pp. 94–99. DOI: 10.1016/J.MEHY.2019.02.035.
[14] S. A. Ganai, S. Mohan, and S. A. Padder, 2025. Exploring novel and potent glycogen synthase kinase-3? inhibitors through systematic drug designing approach, Sci Rep, vol. 15, no. 1, p. 4118. DOI: 10.1038/S41598-025-85868-5.
[15] G. Rajamani, S. Naqvi, and A. Sharma, 2025. Structure–activity relationship of GSK-3? inhibitors: insight into drug design for Alzheimer’s disease, RSC Med Chem. DOI: 10.1039/D5MD00211G.
[16] A. Suenaga, N. Okimoto, Y. Hirano, and K. Fukui, 2012. An efficient computational method for calculating ligand binding affinities, PLoS One, vol. 7, no. 8. DOI: 10.1371/JOURNAL.PONE.0042846.
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