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<p>A novel androstendiol derivative, monoxetanol (MON), was synthesized from androsta-5,15-diene-3β-ol-17-one via a multistep route and evaluated for its anticancer potential. In vitro cytotoxicity was assessed using an MTT assay against human prostate cancer cell lines PC-3 and LNCaP-AI. MON exhibited marked cytotoxicity, with inhibition rates of 79.8% (PC-3) and 64.7% (LNCaP-AI) at 10.0 μM. To rationalize these effects and explore its therapeutic potential, an integrated in silico approach comprising molecular docking, ADMET prediction, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and density functional theory (DFT) analyses was performed, using abiraterone (ABT) as a reference. Docking results indicated that MON displayed consistently stronger binding affinities toward key oncogenic targets, including epidermal growth factor receptor (EGFR), cytochrome P450 17A1 (CYP17A1), and extracellular signal-regulated kinase 2 (ERK2). ADMET profiling suggested favorable pharmacokinetic properties and drug-likeness, with no major toxicity concerns. MD simulations confirmed the conformational stability of MON–protein complexes, supported by favorable MM/PBSA binding free energies predominantly driven by van der Waals and electrostatic contributions. Per-residue decomposition highlighted a broader and more favorable interaction network for MON, particularly within CYP17A1 and ERK2 active sites. DFT calculations further revealed a larger HOMO–LUMO energy gap for MON than ABT in both gas and aqueous phases, indicating enhanced chemical stability. Collectively, these findings position MON as a promising lead scaffold for further optimization and experimental validation in prostate cancer therapy.</p>

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Integrated in silico investigation of an androstendiol derivative (monoxetanol) as a potential anti-prostate cancer agent: insights from molecular docking, MD simulations, MM/PBSA, ADMET, and DFT analyses

  • 期刊论文

  • 发表日期：

    2026年5月7日

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  • Yahia Bekkar,
  • Lanez Elhafnaoui,
  • Najim A. Al-Masoudi,
  • Nabeel A. Abdul-Rida,
  • Wasfi A. Al-Masoudi,
  • Ali M. Mahdi

摘要

A novel androstendiol derivative, monoxetanol (MON), was synthesized from androsta-5,15-diene-3β-ol-17-one via a multistep route and evaluated for its anticancer potential. In vitro cytotoxicity was assessed using an MTT assay against human prostate cancer cell lines PC-3 and LNCaP-AI. MON exhibited marked cytotoxicity, with inhibition rates of 79.8% (PC-3) and 64.7% (LNCaP-AI) at 10.0 μM. To rationalize these effects and explore its therapeutic potential, an integrated in silico approach comprising molecular docking, ADMET prediction, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and density functional theory (DFT) analyses was performed, using abiraterone (ABT) as a reference. Docking results indicated that MON displayed consistently stronger binding affinities toward key oncogenic targets, including epidermal growth factor receptor (EGFR), cytochrome P450 17A1 (CYP17A1), and extracellular signal-regulated kinase 2 (ERK2). ADMET profiling suggested favorable pharmacokinetic properties and drug-likeness, with no major toxicity concerns. MD simulations confirmed the conformational stability of MON–protein complexes, supported by favorable MM/PBSA binding free energies predominantly driven by van der Waals and electrostatic contributions. Per-residue decomposition highlighted a broader and more favorable interaction network for MON, particularly within CYP17A1 and ERK2 active sites. DFT calculations further revealed a larger HOMO–LUMO energy gap for MON than ABT in both gas and aqueous phases, indicating enhanced chemical stability. Collectively, these findings position MON as a promising lead scaffold for further optimization and experimental validation in prostate cancer therapy.