Molecular Docking and Dynamics Based Analysis for the Identification of Novel Inhibitors for Human Parkin G319A Using Computational Approaches

Background: Parkinson's disease (PD) is the second most complex neurodegenerative disorder associated with the loss of dopaminergic neurons and has an unknown etiology. Several pathogenic mechanisms including inflammation, oxidative stress, protein dysfunction, apoptosis, mitochondrial dysfunction, abnormal alpha-synuclein, and autophagy are associated with this dis-order. The current existing medications show limited efficacy and adverse health effects. Hence, in such a scenario, phytocom-pounds can provide an alternate way of effective treatment by repurposing these natural molecules using computational based approaches. Methods: In this study, we explored various plant bioactives as possible inhibitors against the Parkin gene using in silico ap-proaches. In the present study, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the bioactives were determined via predicting small-molecule pharmacokinetic properties (pkCSM). Moreover, the evaluation of molecular docking, dynamics, binding pockets, and protein-protein interactions of the protein was determined via AutoDock Vina, WEBnm@, Computed Atlas of Surface Topography of Proteins (CASTp), and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Results: The findings obtained from molecular docking analysis revealed that Cytochalasin E was the most effective bioactive compound that showed the highest binding affinity of -8.6 kcal/mol when docked against the selected protein. In this study, all the bioactives followed Lipinski's rule of five except Sitoindoside IX. The CASTp tool identified the binding pockets in the protein with the top binding site having an accessible surface (AS) area of 250.39 angstrom 2 and an accessible surface (AS) volume of 203.03 angstrom 3 respectively. STRING tool determined the protein-protein interactions by visualizing protein structure. Conclusion: The findings obtained from this study suggest that Cytochalasin E could be repurposed as a potential inhibitor tar-geting Parkin and these outcomes may prove significant in the process of drug designing. However, further in vitro and in vivo studies are required to validate these results.