In silico evaluation of procyanidin as a potential ESR1 inhibitor: docking and MD insights in uterine fibroids and endometriosis

These are two of the most common gynecologic diseases, affecting 15% to 80% of women of childbearing age diseases. The existing treatments, such as hormonal drugs and selective estrogen receptor modulators like raloxifene, have side effects and recurrence, and thus indicate the need for less harmful non-hormonal therapies. Therefore, this study aimed at exploring plant-derived secondary metabolites as potential ESR1 inhibitors by focusing on the identification of natural ligands characterized by high binding affinity and structural stability and by providing preliminary insights into pharmacokinetic and safety aspects via in silico analysis. Forty structurally diverse phytochemicals were docked into the ESR1 ligand-binding pocket using AutoDock Vina and PyRx, with raloxifene as reference. Procyanidin, the top-scoring ligand, was selected for molecular dynamics (MD) simulations (100 ns, GROMACS) under physiological conditions. Structural stability was assessed by RMSD, RMSF, SASA, and radius of gyration (Rg), while ligand retention was evaluated using center-of-mass (COM) and minimum distance analyses. Three independent 10-ns replicates were also performed to ensure reproducibility of MD results. Procyanidin outperformed raloxifene (− 11.1 kcal/mol) and other options like hesperidin and sanguinarine with the strongest binding (− 12.1 kcal/mol). Docking revealed hydrophobic interactions with Leu387 and Ala350 and hydrogen bonding with Glu353 and Arg394. MD simulations confirmed stable ESR1–procyanidin complexes, with constant RMSD and Rg, stable SASA, and limited flexibility of key binding residues. COM and distance analyses established long-term retention of the ligand, supported by hydrophobic and π–stacking over stable hydrogen bond-dominant binding. Binding free energy analysis (MM-PBSA) further verified a spontaneous and favorable interaction (ΔG_total = − 22.66 kJ mol−1), mainly driven by van der Waals and hydrophobic forces. Procyanidin is a phytochemical lead that shows promise for controlling ESR1 signaling in fibroids and endometriosis as a non-hormonal candidate. Procyanidin emerged as a promising in-silico lead for ESR1 modulation, showing high binding affinity and dynamic stability; nevertheless, further pharmacokinetic, ADMET, and experimental validation are required to substantiate its therapeutic potential. Graphical abstract Similar content being viewed by others Data availability No datasets were generated or analysed during the current study. Abbreviations - ADMET: - Absorption, distribution, metabolism, excretion, and toxicity - BBB: - Blood–brain barrier - COM: - Center of mass - EGCG: - Epigallocatechin gallate - ESR1: - Estrogen receptor 1 - GnRH: - Gonadotropin-releasing hormone - IL-6: - Interleukin 6 - lncRNA: - Long non-coding RNA - MD: - Molecular dynamics simulation - miRNA: - microRNA - NSAIDs: - Nonsteroidal anti-inflammatory drugs - PDB: - Protein Data Bank - PLIP: - Protein–ligand interaction profiler - RA600: - Raloxifene (reference compound) - Rg: - Radius of gyration - RMSD: - Root mean square deviation - RMSF: - Root mean square fluctuation - SASA: - Solvent accessible surface area - SDF: - Structure data file - SERM: - Selective estrogen receptor modulator - SwissADME: - Swiss ADME prediction tool - TGF-β: - Transforming growth factor beta - TIP3P: - Transferable intermolecular potential with 3 points - TNF-α: - Tumor necrosis factor-alpha - VEGF: - Vascular endothelial growth factor

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Material preparation, data collection, and analysis were performed by Zahra Maravandi, Sahar Gholamian, and Ali Samadi. Molecular docking simulations were primarily conducted by Zahra Maravandi. Molecular dynamics simulations and interaction profiling were primarily conducted by Sahar Gholamian, who also handled graphic design for figures and visualizations. Transcriptomic analysis and ADMET profiling were overseen by Ali Samadi, who served as the corresponding author and handled funding acquisition and project management. The first draft of the manuscript was written by Zahra Maravandi. Ali Samadi, and Jeffrey D. Gross provided critical revisions, clinical insights, and edits for the final version. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Corresponding author Ethics declarations Competing interests The authors declare no competing interests. Ethical approval The Ethics Committee of Bam University of Medical Sciences approved this study (Ethical code # IR.MUBAM.REC.1404.043). The research also followed the tenets of the Declaration of Helsinki. This study was extracted from a research project was conducted in Bam University of Medical Sciences. Additionally, ethical issues (including plagiarism, data fabrication and double publication) have been completely observed by the authors. 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 Maravandi, Z., Gholamian, S., Samadi, A. et al. In silico evaluation of procyanidin as a potential ESR1 inhibitor: docking and MD insights in uterine fibroids and endometriosis. In Silico Pharmacol. 14, 29 (2026). https://doi.org/10.1007/s40203-025-00541-z Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s40203-025-00541-z