Pharmacoinformatic-guided Drug Reprofiling for Unveiling of NovelBioactive Inhibitors Targeting USP13 in the Treatment of Parkinson’s Disease

Parkinson’s disease (PD) is an incapacitating neurodegenerative condition caused by the deterioration of dopaminergic neurons and the build-up of $\alpha$-synuclein, which is most common in the aged population and is influenced by an intricate relationship between environmental and genetic components. This research attempts to address the lacuna in definitive treatment strategies for PD by exploring innovative therapeutic targets. The focus centers on Ubiquitin-Specific Protease 13 (USP13), widely distributed in human cells and displaying heightened levels in postmortem PD midbrains, suggesting a pivotal role in disease etiology. Experimental findings underscore USP13’s intricate involvement, negatively regulating Parkin and $\alpha$-synuclein, thereby intricately influencing motor function and dopaminergic neuron survival.Employing advanced molecular docking analyses through PyRx, this research seeks to uncover novel USP13 inhibitors surpassing the efficacy of Spautin-1. An added layer of practicality is introduced through the repurposing of FDA-approved drugs, accentuating the potential for therapeutic intervention. Docking-based virtual screening of 3674 FDAapproved drugs against USP13 identified 144 compounds that met the defined criteria of Binding Energy. Of these, 60 exhibited BBB permeability. The top 10 ligands with the highest negative binding energies and BBB permeability were shortlisted for further analysis.Detailed scrutiny of the top three ligands illuminates AlgestoneAcetophenide’s solubility challenges, while the dopamine antagonist properties of Biriperone raise prudent concerns regarding its suitability for PD intervention. In stark contrast, Canrenone, a clinically established agent for hyperaldosteronism and heart failure, emerges as a compelling candidate with the potential to inhibit USP13 and exert a transformative impact on PD pathology.