Abstract
Prolyl oligopeptidase (POP) is a serine protease that is responsible for the maturation and degradation of short neuropeptides and peptide hormones. The inhibition of POP has been demonstrated in the treatment of α-synucleinopathies and several neurological conditions. Therefore, ligand-based and structure-based pharmacophore models were generated and validated in order to identify potent POP inhibitors. Pharmacophore-based and docking-based virtual screening of a drug-like database resulted in 20 compounds. The in vitro POP assays indicated that the top scoring compounds obtained from virtual screening, Hit 1 and Hit 2 inhibit POP activity at a wide range of concentrations from 0.1 to 10 µM. Moreover, treatment of the hit compounds significantly reduced the α-synuclein expression in SH-SY5Y human neuroblastoma cells, that is implicated in Parkinson's disease. Binding modes of Hit 1 and Hit 2 compounds were explored through molecular dynamics simulations. A detailed investigation of the binding interactions revealed that the hit compounds exhibited hydrogen bond interactions with important active site residues and greater electrostatic and hydrophobic interactions compared to those of the reference inhibitors. Finally, our findings indicated the potential of the identified compounds for the treatment of synucleinopathies and CNS related disorders.