Identification of high-affinity inhibitors for epoxide hydrolase 2 from repurposed drugs in Parkinson’s disease therapeutics

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.