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

doi:10.1016/j.jmgm.2021.108116

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

J Mol Graph Model. 2022 May:112:108116. doi: 10.1016/j.jmgm.2021.108116. Epub 2021 Dec 27.

Affiliations

¹ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
² Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia; School of Science, STEM College, RMIT University, VIC, 3001, Australia.
³ School of Science, STEM College, RMIT University, VIC, 3001, Australia.
⁴ Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3052, Australia.
⁵ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia. Electronic address: Alison.Anderson1@monash.edu.

PMID: 35026665
DOI: 10.1016/j.jmgm.2021.108116

Abstract

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.

Keywords: Alpha-lipoic acid; Drug resistance; Epilepsy; Manganese superoxide dismutase; Molecular docking; Molecular simulations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antioxidants / pharmacology
Epilepsy* / drug therapy
Humans
Molecular Docking Simulation
Oxidation-Reduction
Thioctic Acid* / metabolism
Thioctic Acid* / pharmacology

Substances

Antioxidants
Thioctic Acid