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<p>Nearly 70% of all cases of breast cancer are hormone receptor-positive (HR⁺) breast cancer, which continues to pose a significant clinical challenge because of the development of resistance to traditional endocrine therapies. The current study investigates the possibility of repurposing clinically approved antiviral drugs as alternative modulators of the progesterone receptor (PR) and estrogen receptor α (ERα) in order to address this. Hierarchical molecular docking, followed by network pharmacology, MM/GBSA free-energy estimation, normal-mode analysis (NMA), and molecular dynamics (MD) simulations, were used to screen 90 antiviral medications that represented 13 pharmacological classes. Valganciclovir had the best binding affinity for ERα (–9.118&#xa0;kcal mol⁻¹) among the compounds that were screened. It formed hydrophobic contacts with Leu387, Leu525, and Met421, as well as stable hydrogen-bond interactions with the canonical triad residues Glu353, Arg394, and His524. With protein RMSD kept within 1.8–2.2 Å and ligand RMSD kept between 2.0 and 3.5 Å, MD simulations verified complex stability over 100 ns. Valganciclovir–PR interactions, on the other hand, showed greater dynamic fluctuations (ligand RMSD ≈ 3.0–5.5 Å) and were weaker (–7.673&#xa0;kcal mol⁻¹). The Valganciclovir–ERα complex’s binding free energy, as determined by MM/GBSA analysis, was − 44.50&#xa0;kcal mol⁻¹, supporting strong electrostatic and van der Waals stabilization. In accordance with tighter engagement, NMA showed more conformational restriction upon ERα binding (ΔS = − 9.1&#xa0;kcal mol⁻¹ K⁻¹) than PR (ΔS = − 7.4&#xa0;kcal mol⁻¹ K⁻¹). Ten hub genes (GAPDH, AKT1, TNF, EGFR, HIF1A, BCL2, MTOR, GSK3B, MAPK1, and PIK3CA) involved in PI3K/AKT, MAPK, ErbB, and HIF-1 signaling were highlighted among the 142 shared targets between Valganciclovir and genes linked to breast cancer that were found by network pharmacology. In vitro validation in MCF-7 breast cancer cells demonstrated dose-dependent cytotoxicity with an IC₅₀ of 19.43&#xa0;µg/mL. Quantitative real-time PCR analysis revealed downregulation of ERα (0.76-fold) and upregulation of PR-B (1.36-fold) following treatment, supporting the predicted receptor-targeting mechanism. Collectively, these findings suggest that Valganciclovir may act as a dual-modality modulator—directly stabilizing ERα in an inactive conformation and indirectly attenuating downstream oncogenic signaling—thereby offering a promising scaffold for the development of next-generation endocrine therapeutics in HR⁺ breast cancer.</p>

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A comparative in silico and in vitro analysis of antiviral agents targeting estrogen and progesterone receptors in breast cancer

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  • 发表日期：

    2026年4月11日

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  • Uma Maheshwari Mugundan,
  • Venkatesan Saravanan,
  • Rajanandh Muhasaparur Ganesan

摘要

Nearly 70% of all cases of breast cancer are hormone receptor-positive (HR⁺) breast cancer, which continues to pose a significant clinical challenge because of the development of resistance to traditional endocrine therapies. The current study investigates the possibility of repurposing clinically approved antiviral drugs as alternative modulators of the progesterone receptor (PR) and estrogen receptor α (ERα) in order to address this. Hierarchical molecular docking, followed by network pharmacology, MM/GBSA free-energy estimation, normal-mode analysis (NMA), and molecular dynamics (MD) simulations, were used to screen 90 antiviral medications that represented 13 pharmacological classes. Valganciclovir had the best binding affinity for ERα (–9.118 kcal mol⁻¹) among the compounds that were screened. It formed hydrophobic contacts with Leu387, Leu525, and Met421, as well as stable hydrogen-bond interactions with the canonical triad residues Glu353, Arg394, and His524. With protein RMSD kept within 1.8–2.2 Å and ligand RMSD kept between 2.0 and 3.5 Å, MD simulations verified complex stability over 100 ns. Valganciclovir–PR interactions, on the other hand, showed greater dynamic fluctuations (ligand RMSD ≈ 3.0–5.5 Å) and were weaker (–7.673 kcal mol⁻¹). The Valganciclovir–ERα complex’s binding free energy, as determined by MM/GBSA analysis, was − 44.50 kcal mol⁻¹, supporting strong electrostatic and van der Waals stabilization. In accordance with tighter engagement, NMA showed more conformational restriction upon ERα binding (ΔS = − 9.1 kcal mol⁻¹ K⁻¹) than PR (ΔS = − 7.4 kcal mol⁻¹ K⁻¹). Ten hub genes (GAPDH, AKT1, TNF, EGFR, HIF1A, BCL2, MTOR, GSK3B, MAPK1, and PIK3CA) involved in PI3K/AKT, MAPK, ErbB, and HIF-1 signaling were highlighted among the 142 shared targets between Valganciclovir and genes linked to breast cancer that were found by network pharmacology. In vitro validation in MCF-7 breast cancer cells demonstrated dose-dependent cytotoxicity with an IC₅₀ of 19.43 µg/mL. Quantitative real-time PCR analysis revealed downregulation of ERα (0.76-fold) and upregulation of PR-B (1.36-fold) following treatment, supporting the predicted receptor-targeting mechanism. Collectively, these findings suggest that Valganciclovir may act as a dual-modality modulator—directly stabilizing ERα in an inactive conformation and indirectly attenuating downstream oncogenic signaling—thereby offering a promising scaffold for the development of next-generation endocrine therapeutics in HR⁺ breast cancer.