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.