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Purpose <p>Phosphodiesterase 4 (PDE4) is a validated therapeutic target for inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, the clinical utility of currently approved non-selective PDE4 inhibitors is limited by dose-dependent adverse effects, particularly nausea and vomiting. Selective inhibition of the PDE4B isoform is therefore considered a promising strategy to retain anti-inflammatory efficacy while minimizing PDE4D-mediated side effects.</p> Method <p>To address this challenge, we explored ginger-derived phenolic compounds as natural scaffolds for the design of selective PDE4B inhibitors using a structure-based in silico workflow. Molecular docking of eight gingerol derivatives identified 10-gingerol as the top candidate, showing preferential binding affinity toward PDE4B over PDE4D.</p> Results <p>Subsequent 500 ns molecular dynamics simulations confirmed the stability of the 10-gingerol–PDE4B complex and revealed critical selectivity-determining interactions. Energy decomposition analysis highlighted LEU502, PHE506, and ILE259 as key hydrophobic residues that contribute to PDE4B preference. The phenolic methoxy group and aliphatic chain of 10-gingerol at the R1 and R2 positions formed favorable van der Waals interactions and persistent contacts, which were substantially weaker in PDE4D, explaining the reduced affinity toward that isoform. These mechanistic insights guided the rational design of these modified analogues with improved predicted PDE4B selectivity.</p> Conclusion <p>This study establishes a mechanistic basis for ginger phenolic targeting of PDE4B and provides a computationally driven framework for developing safer, isoform-selective PDE4B inhibitors. The findings support advancing gingerol-based derivatives as innovative anti-inflammatory leads with reduced adverse-effect liability, contributing to pharmaceutical innovation in respiratory drug discovery.</p> Graphical Abstract <p></p>

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Structure-based Insights into PDE4B-Selective Inhibition by Ginger Phenolics: An Integrated Molecular Docking and Dynamics Study

  • 期刊论文

  • 发表日期：

    2026年4月17日

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  • Anis Najwa Abdul Rani,
  • Anand Gaurav,
  • Vannajan Sanghiran Lee,
  • Ruzana Yahya,
  • Nadiah Mad Nasir,
  • Vaishali M. Patil,
  • Ming Tatt Lee

摘要

Purpose

Phosphodiesterase 4 (PDE4) is a validated therapeutic target for inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, the clinical utility of currently approved non-selective PDE4 inhibitors is limited by dose-dependent adverse effects, particularly nausea and vomiting. Selective inhibition of the PDE4B isoform is therefore considered a promising strategy to retain anti-inflammatory efficacy while minimizing PDE4D-mediated side effects.

Method

To address this challenge, we explored ginger-derived phenolic compounds as natural scaffolds for the design of selective PDE4B inhibitors using a structure-based in silico workflow. Molecular docking of eight gingerol derivatives identified 10-gingerol as the top candidate, showing preferential binding affinity toward PDE4B over PDE4D.

Results

Subsequent 500 ns molecular dynamics simulations confirmed the stability of the 10-gingerol–PDE4B complex and revealed critical selectivity-determining interactions. Energy decomposition analysis highlighted LEU502, PHE506, and ILE259 as key hydrophobic residues that contribute to PDE4B preference. The phenolic methoxy group and aliphatic chain of 10-gingerol at the R1 and R2 positions formed favorable van der Waals interactions and persistent contacts, which were substantially weaker in PDE4D, explaining the reduced affinity toward that isoform. These mechanistic insights guided the rational design of these modified analogues with improved predicted PDE4B selectivity.

Conclusion

This study establishes a mechanistic basis for ginger phenolic targeting of PDE4B and provides a computationally driven framework for developing safer, isoform-selective PDE4B inhibitors. The findings support advancing gingerol-based derivatives as innovative anti-inflammatory leads with reduced adverse-effect liability, contributing to pharmaceutical innovation in respiratory drug discovery.

Graphical Abstract