EXPLORING PHYTOCHEMICALS FOR PARKINSON'S THERAPEUTICS THROUGH IN-SILICO DRUG DISCOVERY AND REPURPOSING T0 TARGET VPS35 AND ALPHA-SYNUCLEIN

Abstract

Background: PD is a neurodegenerative conditions that is characterized by the loss in the DA neurons in substantia nigra, that causes motor manifestations such as tremors, rigidity, bradykinesia, and postural instability. Recent studies can highlight the role of mutations, particularly in VPS35 gene, for the development of PD. This study aims to identify potential inhibitors of the VPS35(D620N) protein using an in- silico approach. The research focused on investigating the drug-likeness and pharmacokinetics of select phytochemicals with notable BBB permeability and high gastrointestinal (GI) absorption to identify potential therapeutic agents. Initially, a library of 1,580 phytochemicals from various medicinal plants was screened for checking the Lipinski's rule by Swiss ADME tool . Following this, binding interactions were analyzed with Discovery Studio Visualizer, and blind docking simulations using PyRx, with docking parameters calibrated to align with the reference drug's scoring system. Docking scores were validated using CB-Dock2. Toxicity analysis can be done using PkCSM. Swiss ADME was used to predict ADMET properties. Carcinogenicity assessments can be done using CarcinoPred-EL. Result: Five phytochemicals namely Luteoxanthin, Isowithametelin, Withametelin, Withametelin B, Diosgenin, Daturilinol and Sarsasapogenin derived from the selected medicinal plants show potential as drug candidates for PD. Additionally two more compounds Withanolide A and Hederagenin, can show high GI absorption and thus can be a potential inhibitor against the Vps35(D620N) as act as α-synuclein aggregates inhibitiors in the gut. Findings demonstrate that these compounds can these are ideal candidate for therapeutics in Parkinson’s disease. Conclusion: Several phytochemical compounds found in medicinal plants have shown promise as potential drug candidates for treating Parkinson's disease associated with the mutant VPS35 (D620N). This potential is due to their demonstrated low binding energy and stability when interacting with the target protein.