In silico study of α-synuclein pathology in Parkinson's disease and the potential of H2O2 as complementary therapy
Athiyah Layla, Sri Widyarti, Sutiman Bambang Sumitro
Abstract
Context: Parkinson's disease (PD) is caused by protein aggregates composed of α-synuclein (αSyn) and associated pathologies, such as mitochondrial dysfunction, loss of dopamine neurons, dysregulation of the dopamine transporter (DAT), and absorption of αSyn. Treatment with L-DOPA alone cannot fully address these pathologies, necessitating complementary therapy with low-dose H₂O₂.
Aims: To evaluate the potential of H₂O₂ as a complementary therapy alongside L-DOPA.
Methods: The three-dimensional (3D) structures of ligands and protein targets were retrieved from PubChem and Protein Data Bank (PDB). H₂O₂, as a ligand, was converted using Open Babel integrated with PyRx v.0.9.8. Molecular docking was performed using AutoDock Vina as a plug-in within PyRx v.0.9.8. Docking visualization results were analyzed with PyMOL v.2.5.5 (Schrodinger, LLC) and Discovery Studio 2021 Client v21.1.0.20298. Protein-protein docking was conducted using the HDOCK server (Lab of Biophysics and Molecular Modeling, Huazhong University). Molecular dynamics simulations were carried out using YASARA Structure v.23.9.29.
Results: H₂O₂ demonstrated the ability to prevent αSyn fibril formation by reducing the binding affinity between αSyn proteins. It mitigated mitochondrial dysfunction and loss of dopamine neurons by preventing αSyn binding to VDAC. Dysregulation of the dopamine transporter (DAT) was avoided as H₂O₂ inhibited αSyn binding to DAT and its uptake by preventing αSyn binding to LRP1.
Conclusions: Low-dose H₂O₂ shows potential as a complementary therapy with L-DOPA for Parkinson's disease.
Keywords: α-synuclein; bioinformatics; hydrogen peroxide; neurodegenerative disease.