Investigation of novel chemical scaffolds targeting prolyl oligopeptidase for neurological therapeutics.

Prolyl oligopeptidase (POP) is a potential therapeutic target for treatment of several neurological disorders and α-synucleinopathies including Parkinson's disease. Most of the known POP inhibitors failed in the clinical trials due to poor pharmacokinetic properties and blood-brain impermeability. Therefore, a training set of 30 structurally diverse compounds with a wide range of inhibitory activity against POP was used to generate a quantitative pharmacophore model, Hypo 3, to identify potential POP inhibitors with desirable drug-like properties. Validations through test set, cost analysis, and Fisher's randomization methods proved that Hypo 3 accurately predicted the known inhibitors among inactive compounds. Hypo 3 was employed as 3D query for virtual screening on an in-house drug-like chemical database containing compounds with good brain permeability and ADMET parameters. Database screening with Hypo 3 resulted in 99 compounds that were narrowed down to 21 compounds through molecular docking. Among them, five compounds were identified in our earlier studies, while two compounds showed in vitro POP inhibition. The current study proposed new 16 virtually screened compounds as potential inhibitors against POP that possess Gold docking score in the range of 64.61-75.74 and Chemscore of -32.25 to -38.35. Furthermore, the top scoring four hit compounds were subjected to molecular dynamics simulations to reveal their appropriate binding modes and assessing binding free energies. The hit compounds interacted with POP effectively via hydrogen bonds with important active site residues along with hydrophobic interactions. Moreover, the hit compounds had key inter-molecular interactions and better binding free energies as compared to the reference inhibitor. A potential new hydrogen bond interaction was discovered between Hit 2 with the Arg252 residue of POP. To conclude, we propose four hit compounds with new structural scaffolds against POP for the lead development of POP-based therapeutics for neurological disorders.