Abstract
Multiple sclerosis (MS) is an autoimmune and inflammatory demyelinating disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. Although numerous studies have been conducted to investigate novel therapeutic targets and lead compounds, few drug choices are available to treat MS patients. The etiology of this disease is still poorly understood. However, oxidative stress is proposed as one of the underlining pathology. The neuronal antioxidant enzyme glutathione peroxidase 4 (GPx4) is responsible for scaffolding toxic peroxide phospholipids and reducing neuronal death within the CNS. Therefore, screening for lead compounds able to activate this essential enzyme might protect neuronal cells from damage and slow the disease progression. This study aimed to identify potential activators of GPx4, an essential inhibitor to ferroptosis, as a novel neuroprotective strategy in MS treatment. For understanding the binding of the four selected compounds to GPX4 protein showing the mechanism of the interaction, molecular docking analysis and molecular dynamic (MD) simulation were used. The study was carried out through various computational methods using Autodock Vina for docking of the protein and ligand and Desmond for MD simulation. The four tested compounds used to activate GPx4 are as follows: ferrostatin, lapatinib, liproxstatin-1, and PKUMDL-LDL-102. Results showed that the lapatinib had greater log P value (6.17) which indicates higher permeability through blood brain barrio (BBB) to exirt the proposed neurological effect. In the molecular docking analysis, the best docking scores was displayed by Lapatinib (−7.6 kcal/mol). Ferrostatin, Lapatinib, and Liproxstatin-1 almost bind in the similar sites of the target protein, while PKUMDL-LC-102 binds at a different site. Furthermore, MD simulation study showed a stable system for lapatinib and liproxstatin-1 as confirmed by RMSD and RMSF values during 100 ns trajectories. Additionally, the most negative ΔG Bind score (the lowest) which considered the best was exhibited by lapatinib (−47.52 Kcal/mol). The test compounds were further inspected for their intersction with GPx4 in terms of hydrophobic, hydrogen and other bonding types beside the stability of these bonds by observing the protein–ligand contact within 100 ns trajectories. Interestingly, the receptor–ligand complex showed deep continuous bands for Lapatinib with Lys127 and Gly128. In conclusion, among the four studied compounds Lapatinib could be a promising scaffold for developing effective leads capable of activating GPx4 and assist in the treatment of MS.