Anti-obesity potential of Eurycoma longifolia: molecular docking and experimental validation in diet-induced obese rats
Abstract
Background: Obesity is associated with hyperlipidemia and enhanced adipogenesis mediated by HMGR and GPDH enzymes. Eurycoma longifolia represents a potential natural therapeutic alternative to statins for obesity management.
Objective: To investigate the anti-obesity potential of E. longifolia compounds through HMGR and GPDH inhibition using integrated in silico and in vivo approaches.
Methods: Molecular docking was performed using AutoDock Vina to evaluate interactions between seven bioactive compounds and HMGR/GPDH proteins. Validation was confirmed by RMSD values below 2 Å. Binding affinities and dissociation constants were analyzed. In vivo study employed Wistar rats fed high-calorie, high-fat diet for 12 weeks, followed by four weeks of E. longifolia extract treatment at varying doses. Body weight and intra-abdominal fat were measured.
Results: Three compounds exhibited binding affinities equivalent to atorvastatin against HMGR (-8.4 kcal/mol). Four compounds demonstrated stronger affinity than metformin against GPDH. Extract administration significantly reduced intra-abdominal fat in a dose-dependent manner (p = 0.000).
Conclusion: E. longifolia compounds demonstrate dual inhibitory potential against HMGR and GPDH through computational modeling, with experimental validation confirming significant reduction in visceral adiposity in obese rats.
References
Emmerich SD, Cheryl DV, Fryar MSP, Bryan S, Ogden CL. Obesity and severe obesity prevalence in adults: United States, August 2021-August 2023. National Center for Health Statistics; 2024. https://doi.org/10.15620/cdc/159281
World Health Organization. World Obesity Day 2022 - accelerating action to stop obesity. WHO; 2022. Available from: https://www.who.int/news/item/04-03-2022-world-obesity-day-2022-accelerating-action-to-stop-obesity
Lui DTW, Ako J, Dalal J, Fong A, Fujino M, Horton A, et al. Obesity in the Asia-Pacific region: current perspectives. J Asian Pac Soc Cardiol. 2024;3:e21. https://doi.org/10.15420/japsc.2023.68
Ferdiana AR, Arfines PP, Aryastami NK. Obesity in urban Indonesia: evidence from the 2007 and 2018 Basic Health Research. Med J Indones. 2024;33:119-27. https://doi.org/10.13181/mji.oa.247183
Roemling C, Qaim M. Disparities in obesity rates among adults: analysis of 514 districts in Indonesia. BMC Public Health. 2022;22:1843. https://doi/org/10.1186/s12889-022-14224-1
Vekic J, Zeljkovic A, Stefanovic A, Jelic-Ivanovic Z, Spasojevic-Kalimanovska V. Obesity and dyslipidemia. Metabolism. 2019;92:71-81. https://doi.org/10.1016/j.metabol.2018.11.005
Klop B, Elte JWF, Cabezas MC. Dyslipidemia in obesity: mechanisms and potential targets. Nutrients. 2013;5:1218-40. https://doi.org/10.3390/nu5041218
Bays HE, Kirkpatrick C, Maki KC, Toth PP, Morgan RT, Tondt J, et al. Obesity, dyslipidemia, and cardiovascular disease: a joint expert review from the Obesity Medicine Association and the National Lipid Association 2024. Obes Pillars. 2024;10:100108. https://doi.org/10.1016/j.obpill.2024.100108
Kotyla P. The role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in modern rheumatology. Ther Adv Musculoskelet Dis. 2010;2:257-69. https://doi.org/10.1177/1759720X10384307
Oh S, Mai XL, Kim J, de Guzman ACV, Lee JY, Park S. Glycerol 3-phosphate dehydrogenases (1 and 2) in cancer and other diseases. Exp Mol Med. 2024;56(5):1066-79. https://doi.org/10.1038/s12276-024-01222-1
Jiang SY, Li H, Tang JJ, Wang J, Luo J, Liu B, et al. Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol. Nat Commun. 2018;9:5138. https://doi.org/10.1038/s41467-018-07590-3
Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;2013:CD004816. https://doi.org/10.1002/14651858.CD004816.pub5
Odden MC, Pletcher MJ, Coxson PG, Thekkethala D, Guzman D, Heller D, et al. Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years or older in the United States. Ann Intern Med. 2015;162:533-41. https://doi.org/10.7326/M14-1430
Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124:328-50. https://doi.org/10.1161/CIRCRESAHA.118.312782
Pedro-Botet J, Núñez-Cortés JM, Flores JA, Rius J. Muscle symptoms related with statin therapy in general practice. Atherosclerosis. 2015;241:e197. https://doi.org/10.1016/j.atherosclerosis.2015.04.957
Ramkumar S, Raghunath A, Raghunath S. Statin therapy: review of safety and potential side effects. Acta Cardiol Sin. 2016;32:631-9. https://doi.org/10.6515/acs20160611a
Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology. 2014;60:679-86. https://doi.org/10.1002/hep.27157
Bang CN, Okin PM. Statin treatment, new-onset diabetes, and other adverse effects: a systematic review. Curr Cardiol Rep. 2014;16:461. https://doi.org/10.1007/s11886-013-0461-4
Kuo PC, Damu AG, Lee KH, Wu TS. Cytotoxic and antimalarial constituents from the roots of Eurycoma longifolia. Bioorg Med Chem. 2004;12:537-44. https://doi.org/10.1016/j.bmc.2003.11.017
Nurani LH, Kumalasari E, Rohman A, Widyarini S. Capsule formulation of ethanolic extract of pasak bumi (Eurycoma longifolia Jack) and its effect on human health vital signs. Tradit Med J. 2017;22:91-6. https://doi.org/10.22146/tradmedj.27919
Nurmeilis N, Woro DA, Soemiati A, Khoirunisa A. Diuretic activity and acute toxicity of combination Eurycoma longifolia extract and irbesartan. Indones J Pharm Sci. 2015;2. https://doi.org/10.15416/ijpst.v2i1.7805
Meng EC, Goddard TD, Pettersen EF, Couch GS, Pearson ZJ, Morris JH, Ferrin TE. UCSF ChimeraX: tools for structure building and analysis. Protein Sci. 2023;32(11):e4792. https://doi.org/10.1002/pro.4792
Shapovalov MV, Dunbrack RL. A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions. Structure. 2011;19(6):844-58. https://doi.org/10.1016/j.str.2011.03.019
Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 2019;15(10):569-89. https://doi.org/10.1038/s41574-019-0242-2
Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: new docking methods, expanded force field, and python bindings. J Chem Inf Model. 2021;61(8):3891-8. https://doi.org/10.1021/acs.jcim.1c00203
Bell EW, Zhang Y. DockRMSD: an open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism. J Cheminform. 2019;11(1):40. https://doi.org/10.1186/s13321-019-0362-7
Vittorio S, Lunghini F, Morerio P, Gadioli D, Orlandini S, Silva P, Martinovic J, Pedretti A, Bonanni D, Del Bue A, Palermo G. Addressing docking pose selection with structure-based deep learning: recent advances, challenges and opportunities. Comput Struct Biotechnol J. 2024;23:2141-51. https://doi.org/10.1016/j.csbj.2024.04.042
Schön A, Madani N, Smith AB, Lalonde JM, Freire E. Some binding-related drug properties are dependent on thermodynamic signature. Chem Biol Drug Des. 2011;77(3):161-5. https://doi.org/10.1111/j.1747-0285.2010.01073.x
Singh S, Singh DB, Gautam B, Singh A, Yadav N. Pharmacokinetics and pharmacodynamics analysis of drug candidates. In: Bioinformatics. Academic Press; 2022. p. 305-16. https://doi.org/10.1016/B978-0-323-89775-4.00001-8
Mohanty M, Mohanty PS. Molecular docking in organic, inorganic, and hybrid systems: a tutorial review. Monatshefte Für Chemie. 2023;154(7):683-707. https://doi.org/10.1007/s00706-023-03076-1
Gesto DS, Pereira CMS, Cerqueira NMFS, Sousa SF. An atomic-level perspective of HMG-CoA-reductase: the target enzyme to treat hypercholesterolemia. Molecules. 2020;25(17):3891. https://doi.org/10.3390/molecules25173891
Laakso M, Fernandes Silva L. Statins and risk of type 2 diabetes: mechanism and clinical implications. Front Endocrinol. 2023;14:1239335. https://doi.org/10.3389/fendo.2023.1239335
Lin SH, Huang KJ, Weng CF, Shiuan D. Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening. Drug Des Dev Ther. 2015;9:3313-24. https://doi.org/10.2147/DDDT.S84641
Ruan J, Li Z, Zhang Y, Chen Y, Liu M, Han L, Zhang Y, Wang T. Bioactive constituents from the roots of Eurycoma longifolia. Molecules. 2019;24(17):3157. https://doi.org/10.3390/molecules24173157
Triawanti, Sanyoto DD, Rosida A, Nur'amin HW, Jangkang GG, Airlangga DI. The effect of pasak bumi (Eurycoma longifolia Jack) ethanol extract on the lipid profile of the rats was induced high-calorie high-fat diet. IOSR J Pharm Biol Sci. 2022;17(1 Suppl 2):1-7. https://doi.org/10.9790/3008-1701020107
Balan D, Chan KL, Murugan D, AbuBakar S, Wong PF. Antiadipogenic effects of a standardized quassinoids-enriched fraction and eurycomanone from Eurycoma longifolia. Phytother Res. 2018;32(7):1332-45. https://doi.org/10.1002/ptr.6069
Swierczynski J, Zabrocka L, Goyke E, Raczynska S, Adamonis W, Sledzinski Z. Enhanced glycerol 3-phosphate dehydrogenase activity in adipose tissue of obese humans. Mol Cell Biochem. 2003;254(1-2):55-9. https://doi.org/10.1023/A:1027332523114
Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutr Res Rev. 2010;23(2):270-99. https://doi.org/10.1017/S0954422410000168
Cesaro A, De Michele G, Fimiani F, Acerbo V, Scherillo G, Signore G, Rotolo FP, Scialla F, Raucci G, Panico D, Gragnano F. Visceral adipose tissue and residual cardiovascular risk: a pathological link and new therapeutic options. Front Cardiovasc Med. 2023;10:1187735. https://doi.org/10.3389/fcvm.2023.1187735
Zhang D, Zheng W, Li X, Liang G, Ye N, Liu Y, Li A, Liu X, Zhang R, Cheng J, Yang H. Investigation of obesity-alleviation effect of Eurycoma longifolia on mice fed with a high-fat diet through metabolomics revealed enhanced decomposition and inhibition of accumulation of lipids. J Proteome Res. 2021;20(5):2714-24. https://doi.org/10.1021/acs.jproteome.1c00015
An H, Jang Y, Choi J, Hur J, Kim S, Kwon Y. New insights into AMPK as a potential therapeutic target in metabolic dysfunction-associated steatotic liver disease and hepatic fibrosis. Biomolecules Therapeutics. 2024;33(1):18. https://doi.org/10.4062/biomolther.2024.177
Copyright (c) 2026 Authors
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
