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Chronic opioid exposure disrupts multiple brain regions involved in reward and motivation, leading to neuroadaptive changes that reinforce addictive behaviours. Emerging evidence suggests that such neuroadaptations may involve epigenetic mechanisms, including histone acetylation regulated by histone deacetylases (HDACs), which could potentially be influenced by opioid binding activity. Among these opioids, fentanyl has drawn particular attention due to its potency up to 100 times stronger than morphine and its increasing involvement in overdose fatalities worldwide. This study explores the possibility that fentanyl and selected derivatives could physically interact with histone deacetylases (HDAC1 and HDAC2) using molecular docking and molecular dynamics (MD) simulations. Our present findings found that the fentanyl derivatives–HDAC1 complexes exhibited binding affinities ranging from −7.95 to −8.37 kcal/mol, whereas fentanyl derivatives–HDAC2 complexes ranged from −8.39 to −8.47 kcal/mol. Molecular dynamics simulations revealed that carfentanil exhibited the most stable conformational behaviour, with RMSD values of 0.19–0.21 nm and Rg values of 1.95–1.99 nm. These findings do not confirm functional inhibition but instead propose a potential receptor-independent interaction that warrants empirical validation. Overall, this in-silico work suggests testable hypotheses regarding how potent opioids might influence histone regulation, providing a framework for future biochemical and pharmacological investigations.

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In Silico Molecular Docking and Molecular Dynamics Simulation of Fentanyl and Its Derivatives Against Histone Deacetylase Enzymes

  • 会议论文

  • 发表日期：

    2026年

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  • Tang Jia Xuan,
  • Ghazi Al Jabal,
  • Muhamad Arif Mohamad Jamali,
  • Muhammad Amirul Asyraf,
  • Mohamad Anuar Ahad

摘要

Chronic opioid exposure disrupts multiple brain regions involved in reward and motivation, leading to neuroadaptive changes that reinforce addictive behaviours. Emerging evidence suggests that such neuroadaptations may involve epigenetic mechanisms, including histone acetylation regulated by histone deacetylases (HDACs), which could potentially be influenced by opioid binding activity. Among these opioids, fentanyl has drawn particular attention due to its potency up to 100 times stronger than morphine and its increasing involvement in overdose fatalities worldwide. This study explores the possibility that fentanyl and selected derivatives could physically interact with histone deacetylases (HDAC1 and HDAC2) using molecular docking and molecular dynamics (MD) simulations. Our present findings found that the fentanyl derivatives–HDAC1 complexes exhibited binding affinities ranging from −7.95 to −8.37 kcal/mol, whereas fentanyl derivatives–HDAC2 complexes ranged from −8.39 to −8.47 kcal/mol. Molecular dynamics simulations revealed that carfentanil exhibited the most stable conformational behaviour, with RMSD values of 0.19–0.21 nm and Rg values of 1.95–1.99 nm. These findings do not confirm functional inhibition but instead propose a potential receptor-independent interaction that warrants empirical validation. Overall, this in-silico work suggests testable hypotheses regarding how potent opioids might influence histone regulation, providing a framework for future biochemical and pharmacological investigations.