Alpha-lipoic acid analogues in the regulation of redox balance in epilepsy: A molecular docking and simulation study

Muhammad Shahid Javaid, Ana Antonic-Baker, Eleni Pitsillou, Julia Liang, Chris French, Andrew Hung, Terence J. O'Brien, Patrick Kwan, Tom C. Karagiannis, Alison Anderson

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5 Citations (Scopus)


Objective: Oxidative stress is one of the pathophysiological mechanisms implicated in drug-resistant epilepsy. Recurrent seizures and prolonged treatment with anti-seizure medicines (ASMs) can produce reactive oxygen species (ROS) resulting in neuronal cell damage, cell toxicity, and cell death. This damage may contribute to the loss of efficacy of anti-seizure medicines. Add-on therapy with antioxidants, neuroimmunophilins, and polyphenols may thus be beneficial in drug-resistant epilepsy. In vitro and in vivo studies have shown a significant improvement in drug efficacy and seizure suppression using co-treatment of anti-seizure medication with naturally available antioxidants including alpha-lipoic acid (α-lipoic acid) from walnut; however, the underlying mechanisms of action remain to be fully understood. Methods: We undertook molecular docking and molecular dynamics simulations to determine whether alpha-lipoic acid and related analogues interacted with the human manganese superoxide dismutase (MnSOD) protein, a member of the oxidative metabolic pathway. The 3D structure of the compounds and the protein were retrieved from protein and chemical databases, binding sites were identified and ligand-protein interactions were performed. Results: Alpha-lipoic acid and various analogues docked within a human MnSOD binding region. Docking results were validated by molecular dynamic simulation. The CMX-2043 analogue showed strong binding with MnSOD compared to alpha-lipoic acid and other analogues. Significance: Our findings provide new insights into additional mechanisms of action, which may in part, account for the antioxidant properties associated with alpha-lipoic acid and related analogues. The results support further in vitro and in vivo evaluation of these compounds to better understand their potential as add-on therapy for ASM treatment in epilepsy.

Original languageEnglish
Article number108116
Number of pages8
JournalJournal of Molecular Graphics and Modelling
Publication statusPublished - May 2022


  • Alpha-lipoic acid
  • Drug resistance
  • Epilepsy
  • Manganese superoxide dismutase
  • Molecular docking
  • Molecular simulations

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