Shamsi Anas, Shahwan Moyad, Khan Sohaib Naseem, Yadav Dharmendra Kumar, Altwaijry Nojood, Islam Asimul, Khan Mohd Shahnawaz
Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, UAE.
Department of Pharmacy, College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Republic of Korea.
J Biomol Struct Dyn. 2025 May 4:1-12. doi: 10.1080/07391102.2025.2497448.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that leads to bradykinesia and rest tremors. While the molecular mechanisms underlying PD are not fully understood, rising evidence shows neuroinflammation as a key factor in dopaminergic neuron damage. The soluble epoxide hydrolase (sEH) has appeared as a key player in neuroinflammation associated with PD which represents itself as a promising drug target. Here, we employed a structure-based virtual screening methodology using repurposed drugs from the DrugBank database to identify high-affinity potential inhibitors of sEH. Results showed that two hit molecules, Fluspirilene and Penfluridol, demonstrated appreciable docking potential and specificity toward the sEH active site. These molecules exhibited favorable pharmacological properties and formed critical interactions with residues essential for sEH activity. Further, all-atom molecular dynamics (MD) simulations followed by principal component analysis and free energy landscape were carried out which provide deeper insights into the conformational stability and interaction mechanisms of sEH in complex with Fluspirilene and Penfluridol. The simulation results indicated that the interaction of sEH with Fluspirilene and Penfluridol contributed to the stabilization of its structure throughout the MD trajectories of 500 ns. These findings collectively suggest that Fluspirilene and Penfluridol hold potential as repurposed leads for the development of sEH inhibitors, which offer therapeutic implications for combating PD and other associated conditions.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质中多巴胺能神经元的丧失，导致运动迟缓及静止性震颤。虽然PD潜在的分子机制尚未完全明确，但越来越多的证据表明神经炎症是多巴胺能神经元损伤的关键因素。可溶性环氧化物水解酶（sEH）已成为与PD相关的神经炎症中的关键参与者，这表明它是一个有前景的药物靶点。在此，我们采用基于结构的虚拟筛选方法，利用DrugBank数据库中的已有药物来识别sEH的高亲和力潜在抑制剂。结果表明，两个命中分子氟司必林和五氟利多，对sEH活性位点表现出可观的对接潜力和特异性。这些分子具有良好的药理特性，并与sEH活性所必需的残基形成关键相互作用。此外，还进行了全原子分子动力学（MD）模拟，随后进行主成分分析和自由能景观分析，这为深入了解sEH与氟司必林和五氟利多复合物的构象稳定性和相互作用机制提供了依据。模拟结果表明，在500纳秒的MD轨迹中，sEH与氟司必林和五氟利多的相互作用有助于其结构的稳定。这些发现共同表明，氟司必林和五氟利多有望作为sEH抑制剂开发的已有药物先导物，为对抗PD及其他相关病症提供治疗意义。
