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Purpose <p>Human epidermal growth factor receptor 2 (HER2) signaling has been implicated in a molecular subset of prostate cancer (PC), particularly in advanced and therapy-resistant disease; however, clinically effective HER2-directed strategies in PC remain limited. Rosolic acid (ROA), a naturally occurring polyphenolic compound with a conjugated aromatic scaffold and favorable physicochemical properties, has not been previously explored as a potential HER2-interacting ligand. This study aimed to investigate the binding characteristics, dynamic stability, and drug-likeness properties of ROA in complex with the HER2 kinase domain using a structure-based computational framework.</p> Methods <p>Molecular docking was performed against the HER2 kinase domain (PDB ID: 3RCD) to evaluate binding orientation and interaction profiles. Molecular dynamics simulations (MDS) were conducted for 200 ns to assess structural stability of the protein-ligand complex. Binding energetics were estimated using the MM-PBSA method, while pharmacokinetic and toxicity properties were predicted using SwissADME and the ProTox-3.0 platform. Density functional theory (DFT) calculations using the GAMESS program were performed to evaluate the electronic characteristics of ROA.</p> Results <p>Docking analysis indicated that ROA occupies the HER2 ATP-binding pocket with a predicted binding affinity of − 8.0&#xa0;kcal/mol, forming a hinge interaction with Met801 and additional hydrophobic and π-mediated contacts within the catalytic region. MDS demonstrated stable complex behavior over the simulation trajectory. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations estimated a binding free energy of approximately − 64.22&#xa0;kJ/mol. In silico ADME predictions suggested favorable drug-likeness characteristics, including predicted gastrointestinal absorption and absence of major structural alerts.</p> Conclusions <p>Although ROA exhibited weaker predicted binding affinity compared with the reference inhibitor, the results indicate that this polyphenolic scaffold can interact with the HER2 kinase domain and maintain stable binding behavior in computational simulations. These findings highlight ROA as a potential scaffold for further medicinal chemistry exploration, although experimental validation will be necessary to determine its biological relevance.</p>

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Computational Investigation of Rosolic Acid as an Inhibitor Targeting HER2 in Prostate Cancer Using Virtual Screening, Molecular Docking, and Molecular Dynamics Simulations

  • 期刊论文

  • 发表日期：

    2026年5月23日

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  • Anirban Goutam Mukherjee,
  • Abilash Valsala Gopalakrishnan

摘要

Purpose

Human epidermal growth factor receptor 2 (HER2) signaling has been implicated in a molecular subset of prostate cancer (PC), particularly in advanced and therapy-resistant disease; however, clinically effective HER2-directed strategies in PC remain limited. Rosolic acid (ROA), a naturally occurring polyphenolic compound with a conjugated aromatic scaffold and favorable physicochemical properties, has not been previously explored as a potential HER2-interacting ligand. This study aimed to investigate the binding characteristics, dynamic stability, and drug-likeness properties of ROA in complex with the HER2 kinase domain using a structure-based computational framework.

Methods

Molecular docking was performed against the HER2 kinase domain (PDB ID: 3RCD) to evaluate binding orientation and interaction profiles. Molecular dynamics simulations (MDS) were conducted for 200 ns to assess structural stability of the protein-ligand complex. Binding energetics were estimated using the MM-PBSA method, while pharmacokinetic and toxicity properties were predicted using SwissADME and the ProTox-3.0 platform. Density functional theory (DFT) calculations using the GAMESS program were performed to evaluate the electronic characteristics of ROA.

Results

Docking analysis indicated that ROA occupies the HER2 ATP-binding pocket with a predicted binding affinity of − 8.0 kcal/mol, forming a hinge interaction with Met801 and additional hydrophobic and π-mediated contacts within the catalytic region. MDS demonstrated stable complex behavior over the simulation trajectory. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations estimated a binding free energy of approximately − 64.22 kJ/mol. In silico ADME predictions suggested favorable drug-likeness characteristics, including predicted gastrointestinal absorption and absence of major structural alerts.

Conclusions

Although ROA exhibited weaker predicted binding affinity compared with the reference inhibitor, the results indicate that this polyphenolic scaffold can interact with the HER2 kinase domain and maintain stable binding behavior in computational simulations. These findings highlight ROA as a potential scaffold for further medicinal chemistry exploration, although experimental validation will be necessary to determine its biological relevance.