Targeting GnRHR and ESR-1 Receptors with Natural Bioactive Compounds: A Network Pharmacology and Molecular Docking Approach to Endometriosis Therapy

Endometriosis is a chronic inflammatory disorder linked to ectopic endometrial tissue and increased estradiol, resulting in pain, infertility, and decreased quality of life. Current treatments primarily use gonadotropin-releasing hormone receptor (GnRHR) antagonists and hormonal therapies to lower estrogen, but long-term use can lead to hypoestrogenic side effects and safety concerns. GnRHR antagonists, such as relugolix, are effective but limited to one hormonal pathway, indicating the necessity for alternative strategies that engage broader molecular mechanisms. This study utilized network pharmacology and structure-based computational methods to identify phytochemical candidates that may be relevant for treating endometriosis. Disease-associated genes were analyzed using protein-protein interaction (PPI) networks, identifying estrogen receptor alpha (ESR1) and GnRHR as key hub proteins in regulating pathways related to endometriosis. Bioactive compounds were screened from natural product databases. Molecular docking studies indicated that three phytochemicals, such as 8-(3’,4’-dimethoxyphenyl)-2-methoxynaphtho-1,4-quinone, atherosperminine, and picrasidine N, showed binding affinities to GnRHR similar to relugolix and stable interactions with ESR1, unlike relugolix. In silico predictions indicate an acceptable safety profile for pharmacokinetics, drug-likeness, and toxicity, with no predicted carcinogenic or cytotoxic risks; however, some parameters require experimental validation due to uncertainty. These findings provide preliminary in silico evidence for a dual-targeting strategy involving GnRHR and ESR1, distinguishing it from current GnRHR therapies and suggesting potential lead compounds for further research in endometriosis. Similar content being viewed by others Data Availability NA. Abbreviations - ADMET: - Absorption distribution metabolism excretion and toxicity - aPTT: - Activated partial thromboplastin time - BP: - Biological process - CC: - Cellular component - CRP: - C-reactive protein - CYP19A1: - Cytochrome P450 family 19 subfamily a member 1 - ESR1, ESR2: - Estrogen receptor 1 and 2 - ERα: - Estrogen receptor alpha - ETP: - Endogenous thrombin potential - GnRH: - Gonadotropin-releasing hormone - GnRHR: - Gonadotropin-releasing hormone receptor - GO: - Gene ontology - GSTM1: - Glutathione S-transferase Mu 1 - IL1B, IL6: - Interleukin 1 beta, interleukin 6 - IMPPAT: - Indian medicinal plants, phytochemistry, and therapeutics - LH: - Luteinizing hormone - MF: - Molecular function - MMP2: - Matrix metallopeptidase 2 - MRI: - Magnetic resonance imaging - NSAIDs: - Non-steroidal anti-inflammatory drugs - NLR: - Neutrophil-lymphocyte ratio - OMIM: - Online Mendelian inheritance in man - PDB: - Protein data bank - PPI: - Protein-protein interaction - PTGS2: - Prostaglandin-endoperoxide synthase 2 - STRING: - Search tool for the retrieval of interacting genes/proteins - TP53: - Tumor protein 53 - vWF: - Von willebrand factor - WNT4: - Wingless-type MMTV integration site family member 4

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The authors thank the VIT, Vellore, Tamil Nadu, India, for supporting this work. Funding This research received no external funding. Author information Authors and Affiliations Contributions Conceptualization: Piyush Jagdish Balgote, Ketaki Neelesh Apte, Bhargawi Rajendra Apte, Savani Jayant Pathak; Study design: Piyush Jagdish Balgote, Ketaki Neelesh Apte, Jayanthi Sivaraman; Methodology and computational analysis: Piyush Jagdish Balgote, Ketaki Neelesh Apte, Bhargawi Rajendra Apte; Formal analysis-Piyush Jagdish Balgote, Ketaki Neelesh Apte, Bhargawi Rajendra Apte, Savani Jayant Pathak; Critical analysis- Piyush Jagdish Balgote, Jayanthi Sivaraman; Visualization and figure preparation: Ketaki Neelesh Apte, Bhargawi Rajendra Apte, Savani Jayant Pathak; Writing—original draft preparation: Piyush Jagdish Balgote, Ketaki Neelesh Apte, Bhargawi Rajendra Apte, Savani Jayant Pathak; Writing—review and editing: - Piyush Jagdish Balgote; Resources: Piyush Jagdish Balgote, Ketaki Neelesh Apte, Bhargawi Rajendra Apte; Supervision and project guidance: Jayanthi Sivaraman; Project administration: Jayanthi Sivaraman. All authors have approved the final manuscript version and accept accountability for the work's aspects. Corresponding author Ethics declarations Conflict of interest The authors declared no potential conflicts of interest concerning this article’s research, authorship, and publication. Ethics Approval and Consent to Participate NA. Consent for Publication We assure you this manuscript has not been published in part or whole and is not under consideration for publication elsewhere in any language. All the authors have thoroughly studied the manuscript and approved its consent and submission to the “Indian Journal of Clinical Biochemistry” journal. Informed Consent NA. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Balgote, P.J., Apte, K.N., Apte, B.R. et al. Targeting GnRHR and ESR-1 Receptors with Natural Bioactive Compounds: A Network Pharmacology and Molecular Docking Approach to Endometriosis Therapy. Ind J Clin Biochem (2026). https://doi.org/10.1007/s12291-026-01400-0 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s12291-026-01400-0