Molecular Docking and ADMET of Levodopa against Leucine-Rich Repeat Kinases, and In-Vitro Mobility Analysis in C. Elegans for Parkinson's Disease

• Published in: 2023 IEEE 23rd International Conference on Bioinformatics and Bioengineering (BIBE) pp. 369 - 376
• Main Authors: Jatti, Tejaswini, Maniyal, Nidhi, Mouli, Sahana, Shenoy, Rashmi, Bhat, Savithri
• Format: Conference Proceeding
• Language: English
• Published: IEEE 04.12.2023
• Subjects: Behavioral sciences; C. elegans; Discovery studio; Drugs; Image analysis; LD 50; Levodopa; Molecular Docking; Organisms; Paraquat; Parkinson's disease; Pharmacokinetics; Toxicology; Visualization
• ISSN: 2471-7819
• DOI: 10.1109/BIBE60311.2023.00067

Parkinson's Disease (PD) is a neurodegenerative disorder known to reduce Dopamine levels in the brain. Amongst several biological and environmental factors, studies have shown a link between the incidence of PD to the exposure of chemicals found in herbicides such as Paraquat. In the present research, Caenorhabditis elegans has been chosen as the model system to study the effect of Paraquat. The organism has a simple brain anatomy and a small neuronal count. Plant-based medications from legumes containing Levodopa, a precursor of dopamine have been used for many years as the treatment for PD. This aids in restoring the levels of dopamine in the brain. The PD in C. elegans was induced by exposing the organism to various concentrations of Paraquat in the laboratory. In-silico experiments such as docking, ADMET, physicochemical and pharmacokinetic properties were conducted for Paraquat and Levodopa using Swiss ADME and pkCSM (Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures). The molecular docking for receptors human Leucine-rich repeat kinase-2 (LRRK2) and its analog in C. elegans, Leucine-rich repeat serine/threonine-protein kinase-I(LRK1) against the ligands Paraquat and Levodopa is reported. The ligand was docked into the binding site of the receptor and their interaction energies were calculated using binding energy. Further, the complexes were visualized using BIOVIA Discovery Studio Visualizer. The LD 50 of Paraquat on C. elegans was tested and the movement analysis was done using the image processing tool, Image.J, It was found that the LD 50 for an interval of 3 hours was 0.1M. The movement analysis using ImageJ revealed the length and the distance traveled per second by the worm. It was observed that, with the increase in the concentration of Paraquat, the movement was affected. The distance traveled by the worm in 0.1M Paraquat at 0 hours was 192.80 μm and at 3 hours was 88.37 μm, The study provides insights into the toxic effects of Paraquat on C. elegans, especially concerning its behavior and movement. Also, the results obtained from In-silico studies demonstrate that Levodopa could be used as potential therapeutics in the treatment of PD. These findings contribute to an understanding of the potential link between herbicide exposure and the development of PD.