Potent Small Molecules Inhibitors Discovery through Ligand-based Modelling for Effective Treatment of Parkinson’s Disease

Abstract

Background: Parkinson’s disease (PD) is a chronic neurodegenerative disease affecting mostly aged people. The disease's symptoms develop gradually over time and include tremors, bradykinesia, rigidity, and postural instability. Current treatment options for PD are only symptom-targeted. Prolyl oligopeptidase (POP) is a serine protease enzymes implicated in PD pathogenesis via an increase in the aggregation of α-synuclein protein in the brain. Aim: This study aims to identify potent anti-PD ligands with inhibitory potential against POP Methods: Ligand-based pharmacophore modeling, Glide extra precision (XP) docking, and post-simulation analysis methods were used. Results: The adopted ligand-based (LB) modeling generated pharmacophoric features, including 1 hydrophobic group, 1 positive ionizable group, 2 aromatic rings, and 2 hydrogen bond acceptors. A total of 23 hits with a Gunner-Henry score of 0.7 and an enrichment factor of 30.24 were obtained as validation protocols, making it an ideal model. The LB model retrieved 177 hit compounds from the 69,543 natural screening ligands available in the Interbioscreen database. Interestingly, ligands 1, 2, 3, 4, and 5 orderly demonstrated higher binding affinities with Glide XP docking of -9.0, -8.8, -8.7, -8.7, -8.7 kcal/mol compared to reference drugs, GSK552 and ZPP with -8.2, and -6.8 kcal/mol respectively. Similarly, their MM/GBSA values were recorded as -54.4, -51.3, -58.4, -49.3, - 33.5, & -32.5 kJ/mol respectively. Further, MD analysis indicated that ligands had higher favorable binding and stability to the receptor. Conclusion: Overall, the study paves the way for developing potential anti-PD therapeutics. The ligands are recommended as adjuvant/single candidate as anti-PD candidates upon further experiment.