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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Piyush Jagdish Balgote,
  • Ketaki Neelesh Apte,
  • Bhargawi Rajendra Apte,
  • Savani Jayant Pathak,
  • Jayanthi Sivaraman

摘要

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.