TARGETING PINK1 ACTIVATION IN PARKINSON’S DISEASE: UNVEILING THERAPEUTIC POTENTIALS THROUGH DRUG REPURPOSING & IN-SILICO ANALYSIS

Abstract

Aim: The purpose of this study is to investigate the possibility of targeting PTEN-induced kinase 1 (PINK1), a mitochondrial serine/threonine kinase linked to the etiology of Parkinson's disease (PD). Through the initial stages of mitophagy, PINK1 plays a crucial part in mitochondrial quality control and neuronal degeneration which is linked to its malfunction. This investigation mainly focuses on assessing small molecule modulators that can interact with PINK1, given the pressing need for disease-modifying treatments in Parkinson's disease. The binding interactions of Niclosamide, a known FDA-approved drug, and N-[3-[acetyl(methyl)amino] phenyl]-2,4-difluoro-6-hydroxybenzamide (ZINC ID: Z1571042344), a novel compound found by virtual screening of the ZINC database, were evaluated using molecular docking techniques. To find important residues inside PINK1's functional area, active site prediction was carried out using the PrankWeb server. To determine drug-likeness profiles, pharmacokinetic characteristics, and binding affinity, docking simulations were utilized alongside with ADME studies.Result: According to the docking studies, Niclosamide has a binding affinity of -8.1 kcal/mol for the predicted PINK1 active site, whereas the novel molecule has a higher binding affinity of -9.6 kcal/mol. Both substances showed higher binding affinity towards the PINK1 functional domain by interacting with important active site residues like Tyr198, Arg201, and Glu203. According to ADME profiling, the new molecule has better pharmacokinetic characteristics, such as full compliance to Lipinski's Rule of Five, strong gastrointestinal absorption and BBB permeability, a decreased molecular weight, and good drug-likeness. In comparison to Niclosamide, it also showed improved water solubility. Conclusion: The discovery of ZINC1571042344 as a more powerful binder with advantageous drug-like characteristics raises the possibility that it could be used as a substitute lead molecule to target PINK1 in Parkinson's disease. Methods used in this investigation included ADME analysis validation and molecular docking. Thus, suggesting to a successful method for finding new therapeutic agents for Parkinson's disease and offering a positive roadmap for upcoming drug development and experimental validation attempts.