Systems Pharmacology Analysis of an Estrogen-Modulating Polyherbal Formulation for Reversing Age- and Sex-Related Cognitive Decline
DOI:
https://doi.org/10.64229/4n4w8961Keywords:
Alzheimer’s disease, Estrogen receptor-1, Systems pharmacology, Polyherbal phytoformulation, NeuroprotectionAbstract
Background: Alzheimer’s disease (AD) exhibits pronounced sex bias, with estrogen decline emerging as a critical contributor to accelerated cognitive deterioration in aging females. Therapeutic strategies capable of restoring estrogen-mediated neuroprotection without systemic hormone replacement remain an unmet clinical need. Methods: This study employed an integrative systems pharmacology framework to evaluate the estrogen-modulating potential of a rational polyherbal phytoformulation comprising Bacopa monnieri (BM), Hippophae rhamnoides (HR), and Dioscorea bulbifera (DB). ADMET (Absorption, Distribution, Metabolism, Excretion and toxicity) filtered phytoconstituents underwent target prediction, protein-protein interaction topology analysis, Gene Ontology and KEGG enrichment, molecular docking, and molecular dynamics simulations, with mechanistic prioritization centered on estrogen receptor-1 (ESR1). Results: Network analysis identified ESR1 as the dominant hub-bottleneck regulator, functionally linked to steroidogenesis, lipid metabolism, and endocrine signaling. Enrichment profiling confirmed strong convergence toward estrogen receptor signaling, steroid hormone biosynthesis, ovarian steroidogenesis, and endocrine resistance pathways. Structure-based validation demonstrated stable occupation of the ESR1 ligand-binding pocket by four phytoconstituents, with emodin and β-sitosterol showing binding affinities comparable to or exceeding estradiol. Subsequent 25-ns molecular dynamics simulations revealed sustained structural stability and minimal residue-level fluctuations, supporting robust ESR1 engagement. Conclusion: Collectively, these findings define an ESR1-centered, estrogen-restorative neuroprotective mechanism underlying the investigated polyherbal formulation and highlight phytoestrogen-driven multi-target modulation as a promising complementary strategy for age- and sex-associated cognitive decline in AD. This work provides a mechanistically grounded foundation for advancing endocrine-modulating phytotherapeutics toward translational neuroprotection.
References
[1]Rojas-Gutierrez E, Muñoz-Arenas G, Treviño S, Espinosa B, Chavez R, Rojas K, et al. Alzheimer’s disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration. Synapse, 2017, 71(10), e21990. DOI: 10.1002/syn.21990
[2]Egunlusi AO, Joubert J. NMDA receptor antagonists: Emerging insights into molecular mechanisms and clinical applications in neurological disorders. Pharmaceuticals, 2024, 17(5), 639. DOI: 10.3390/ph17050639
[3]Passeri E, Elkhoury K, Morsink M, Broersen K, Linder M, Tamayol A, et al. Alzheimer’s disease: Treatment strategies and their limitations. International Journal of Molecular Sciences, 2022, 23(22), 13954. DOI: 10.3390/ijms232213954
[4]O’Neal MA. Women and the risk of Alzheimer’s disease. Frontiers in Global Women’s Health, 2023, 4, 1324522. DOI: 10.3389/fgwh.2023.1324522
[5]Chowdhury MR, Kumar V, Deepa VS. Unraveling metabolic pathways and key genes in Alzheimer’s, type 2 diabetes, and estrogen dysregulation among aging women: A systems biology approach. Journal of Proteins and Proteomics, 2024, 15, 347-360. DOI: 10.1007/s42485-024-00157-5
[6]Guo H, Liu M, Zhang L, Wang L, Hou W, Ma Y, et al. The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms. Current Neuropharmacology, 2020, 18(6), 485-500. DOI: 10.2174/1570159X18666200123165652
[7]Farkas S, Szabó A, Hegyi AE, Török B, Fazekas CL, Ernszt D, et al. Estradiol and estrogen-like alternative therapies in use: The importance of the selective and non-classical actions. Biomedicines, 2022, 10(4), 861. DOI: 10.3390/biomedicines10040861
[8]Lee BH, Eid RS, Hodges TE, Barth C, Galea LAM. Leveraging research into sex differences and steroid hormones to improve brain health. Nature Reviews Endocrinology, 2025, 21, 214-229. DOI: 10.1038/s41574-024-01061-0
[9]Rajini PS, Muralidhara M. Therapeutic efficacy of ayurvedic polyherbal formulations (PHF): Interactive mechanisms and broad-spectrum activities against neurological disorders. Ayurvedic Herbal Preparations in Neurological Disorders, 2023, 89-111. DOI: 10.1016/B978-0-443-19084-1.00024-7
[10]Chowdhury MR, Tiwari A, Karamveer K, Dubey GP, Tiwary BK, Deepa VS. Clinical application and pharmacological mechanism of polyherbal phytoformulations in breast cancer and depression treatment: Review and network pharmacological analysis. Proceedings of the Indian National Science Academy, 2023, 89(6), 560-583. DOI: 10.1007/s43538-023-00193-7
[11]Chowdhury MR, Reddy RVS, Nampoothiri NK, Erva RR, Vijaykumar SD. Exploring bioactive natural products for treating neurodegenerative diseases: A computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson’s disease. Metabolic Brain Disease, 2025, 40, 169. DOI: 10.1007/s11011-025-01585-y
[12]Wang X, Shi X, Xi Z, Zhang ZT, Luo ZC, Wang J, et al. The scientific basis of synergy in traditional Chinese medicine: Physicochemical, pharmacokinetic, and pharmacodynamic perspectives. Chinese Medicine, 2026, 21, 15. DOI: 10.1186/s13020-025-01291-y
[13]Upadhyay P, Sadhu A, Singh PK, Agrawal A, Ilango K, Purohit S, et al. Revalidation of the neuroprotective effects of a United States patented polyherbal formulation on scopolamine induced learning and memory impairment in rats. Biomedicine & Pharmacotherapy, 2018, 97, 1046-1052. DOI: 10.1016/j.biopha.2017.11.008
[14]Chowdhury MR, Karamveer K, Tiwary BK, Nampoothiri NK. Integrated systems pharmacology, molecular docking, and MD simulations investigation elucidating the therapeutic mechanisms of BHD in Alzheimer’s disease treatment. Metabolic Brain Disease, 2025, 40(1), 8. DOI: 10.1007/s11011-024-01460-2
[15]Huang L, Xie D, Yu Y, Liu H, Shi Y, Shi T, et al. TCMID 2.0: A comprehensive resource for traditional Chinese medicine. Nucleic Acids Research, 2018, 46(D1), 1117-1120. DOI: 10.1093/nar/gkx1028
[16]Vivek-Ananth RP, Mohanraj K, Sahoo AK, Samal A. IMPPAT 2.0: An enhanced and expanded phytochemical atlas of Indian medicinal plants. ACS Omega, 2023, 8(9), 8827-8845. DOI: 10.1021/acsomega.3c00156
[17]Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of small molecules. Scientific Reports, 2017, 7, 42717. DOI: 10.1038/srep42717
[18]Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Journal of Molecular Biology, 2001, 46: 3-26.
[19]Banerjee P, Kemmler E, Dunkel M, Preissner R. ProTox-III: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Research, 2024, 51(W1), W440-W463. DOI: 10.1093/nar/gkae303
[20]Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK. BindingDB: A web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Research, 2007, 35, D198-201. DOI: 10.1093/nar/gkl999
[21]Daina A, Michielin O, Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Journal of Chemical Information and Modeling, 2019, 47(W1), W357-W364. DOI: 10.1093/nar/gkz382
[22]Coudert E, Gehant S, de Castro E, Pozzato M, Baratin D, Neto T, et al. Annotation of biologically relevant ligands in UniProtKB using ChEBI. Bioinformatics, 2023, 39(1), btac793. DOI: 10.1093/bioinformatics/btac793
[23]Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Research, 2021, 49(D1), D605-D612. DOI: 10.1093/nar/gkaa937
[24]Chowdhury MR, Vijaykumar SD. A systems biology approach reveals dual neurotherapeutic mechanisms of Dioscorea bulbifera in Alzheimer’s disease via estrogen signaling and cholinergic modulation. Inflammopharmacology, 2025, 33(9), 5483-5508. DOI: 10.1007/s10787-025-01872-1
[25]Ge SX, Jung D, Yao R. ShinyGO: A graphical gene-set enrichment tool for animals and plants. Bioinformatics, 2020, 36(8), 2628-2629. DOI: 10.1093/bioinformatics/btz931
[26]Kanehisa M, Sato Y. KEGG mapper for inferring cellular functions from protein sequences. Protein Science, 2020, 29(1), 28-35. DOI: 10.1002/pro.3711
[27]Luo W, Brouwer C. Pathview: An R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics, 2013, 29(14), 1830-1831. DOI: 10.1093/bioinformatics/btt285
[28]Saur IML, Panstruga R, Schulze-Lefert P. NOD-like receptor-mediated plant immunity: From structure to cell death. Nature Reviews Immunology, 2021, 21, 305-318. DOI: 10.1038/s41577-020-00473-z
[29]Krieger E, Joo K, Lee J, Lee J, Raman S, Thompson J, et al. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins: Structure, Function, and Bioinformatics, 2009, 77(S9), 114-122. DOI: 10.1002/prot.22570
[30]Goodsell DS, Olson AJ. Automated docking of substrates to proteins by simulated annealing. Proteins: Structure, Function, and Bioinformatics, 1990, 8(3), 195-202. DOI: 10.1002/prot.340080302
[31]Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera__A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 2004, 25(13), 1605-1612. DOI: 10.1002/jcc.20084
[32]Desmond Molecular Dynamics System, Maestro-Desmond Interoperability Tools. D. E. Shaw Research, New York, NY, USA, 2019. Available from: ttps://www.deshawresearch.com/resources_desmond.html (accessed on 27 August 2025).
[33]Schrödinger Suite 2019-1__Protein Preparation Wizard. Epik. Schrödinger, LLC, New York, NY, USA, 2019. Available from: https://www.schrodinger.com (accessed on 10 August 2025).
[34]Banks JL, Beard HS, Cao Y, Cho AE, Damm W, Farid R, et al. Integrated modeling program, applied chemical theory (IMPACT). Journal of Computational Chemistry, 2005, 26(16), 1752-1780. DOI: 10.1002/jcc.20292
[35]Mark P, Nilsson L. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. The Journal of Physical Chemistry A, 2001, 105(43), 9954-9960. DOI: 10.1021/jp003020w
[36]Ghosh S, Derle A, Ahire M, More P, Jagtap S, Phadatare SD, et al. Phytochemical analysis and free radical scavenging activity of medicinal plants Gnidia glauca and Dioscorea bulbifera. PLOS ONE, 2013, 8, e82529. DOI: 10.1371/journal.pone.0082529
[37]Kumar S, Das G, Shin H, Patra JK. Dioscorea spp. (A wild edible tuber): A study on its ethnopharmacological potential and traditional use by the local people of Similipal Biosphere. Frontiers in Pharmacology, 2017, 8, 52. DOI: 10.3389/fphar.2017.00052
[38]Adeniran AA, Sonibare MA. Assessment of genetic fidelity of Dioscorea bulbifera L. and Dioscorea hirtiflora Benth. and medicinal bioactivity produced from the induced tuberous roots. Plant Cell, Tissue and Organ Culture, 2018, 132, 343-357. DOI: 10.1007/s11240-017-1334-0
[39]Marin R, Diaz M. Estrogen interactions with lipid rafts related to neuroprotection: Impact of brain ageing and menopause. Frontiers in Neuroscience, 2018, 12, 128. DOI: 10.3389/fnins.2018.00128
[40]Maioli S, Leander K, Nilsson P, Nalvarte I. Estrogen receptors and the aging brain. Essays in Biochemistry, 2021, 65(6), 913-925. DOI: 10.1042/EBC20200162
[41]Javankiani S, Bolandi S, Soleimani A, et al. MAPK signaling mediates tamoxifen resistance in estrogen receptor-positive breast cancer. Molecular and Cellular Biochemistry, 2025, 480, 4973-4989. DOI: 10.1007/s11010-025-05304-0
[42]Chowdhury MR, Deepa VS, Raja VK. Mapping the pathogenic nexus: Gene overlap and protein interaction networks in Alzheimer’s and breast cancer as a precursor to protein structure prediction and analysis. Advances in Protein Chemistry and Structural Biology, 2025, 147, 275-331. DOI: 10.1016/bs.apcsb.2024.11.007
[43]Cassidy A. Potential risks and benefits of phytoestrogen-rich diets. International Journal for Vitamin and Nutrition Research, 2003, 73, 120-126. DOI: 10.1024/0300-9831.73.2.120
[44]Sarma HN, Sarma I, Misra K, Saikia A, Doima S. Female reproductive health__Regulating hormones and phytosteroids as alternative modulator: A review. 2023.
Downloads
Additional Files
Published
Issue
Section
License
Copyright (c) 2026 Mayank Roy Chowdhury (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
