REPURPOSING PHYTOCHEMICALS FOR LRRK2 G2019S AND Α-SYNUCLEIN MODULATION IN PARKINSON’S DISEASE: A BIOINFORMATICS APPROACH

Abstract

Aim: Parkinson's disease represents a formidable global health challenge due to the deficiency of disease-modifying therapies, and the protracted usage of existing medications like Levodopa (L-dopa) is associated with incapacitating side effects. This investigation engrossed on employing an in-silico methodology to explore the drug likeness and pharmacokinetics of select phytochemicals demonstrating notable permeability across the blood-brain barrier (BBB) and high gastrointestinal (GI) absorption, thereby identifying prospective therapeutic agents. Initially, a meticulously curated collection of 1,580 phytochemicals sourced from diverse medicinal plants underwent virtual screening for observance to Lipinski's Rule of Five applied using SwissADME, followed by scrutinizing binding interactions with Discovery Studio Visualizer, while blind docking simulations were executed employing PyRx, with docking parameters tailored to match the scoring system of a reference drug. Validation of the docking scores was accomplished using CB-Dock2. ADMET properties were prognosticated by means of SwissADME, and assessments of carcinogenicity and toxicity were conducted via CarcinoPred-EL and PkCSM tools, correspondingly. Result: Five compounds, namely Isowithametelin,Yamogenin, Withametelin, Diosgenin, and Withametelin B, exhibiting promising pharmacological properties and low toxicity with high permeability across the BBB, were identified as potential inhibitors of LRRK2, a protein associated with Parkinson's disease. Additionally, two compounds, Withanolide A and Hederagenin, characterized by GI absorption, were also recognized as potential inhibitors of LRRK2 as they act in the gut inhibiting α-syn oligomerization and fibrillation. These compounds demonstrated either no or mild toxicity, indicating their potential for therapeutic application in Parkinson's disease. Conclusion: Approximately of the phytochemical compounds identified in medicinal plants exhibit potential as drug candidates for treating Parkinson's disease caused by the mutant LRRK2 G2019S. This potential is attributed to their chronicled low binding energy and stability when interacting with the target protein.