Computational Drug Discovery for Novel Small Molecule Inhibitors Targeting LRRK2 in Parkinson's Disease Treatment

Abstract

Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the brain, leading to motor and non-motor symptoms. The development of novel pharmacotherapies targeting specific molecular pathways implicated in PD pathogenesis is crucial for disease management. Leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising therapeutic target due to its involvement in both familial and sporadic forms of PD. In this study, we employed computational drug discovery techniques to identify potential small molecule inhibitors targeting LRRK2 for PD treatment. The binding affinities of virtual test compounds with the LRRK2 drug target were assessed, revealing a range of affinities from − 6.8 to -10.2 kcal/mol. Lead compounds, including Compound 7, 14, and 15, exhibited the highest binding affinities (-10.2, -10.1, and − 10.1 kcal/mol, respectively), surpassing those of standard ligands. Molecular docking analysis elucidated the inhibitory properties of selected lead compounds, with C7, C14, and C15 identified as the most potent LRRK2 inhibitors. These compounds demonstrated favorable interactions with specific amino acid residues within the LRRK2 receptor, indicating their potential therapeutic efficacy. The validation of the docking protocol confirmed the accuracy of the computational methodology employed, ensuring reliable predictions of ligand-receptor interactions. Furthermore, the ADMET profile analysis provided insights into the drug-like characteristics and pharmacokinetic properties of selected lead compounds. Despite variations in lipophilicity, water solubility, and bioavailability scores, most test compounds exhibited moderate to high GI absorption potential and skin permeation values, suggesting their suitability for oral administration and blood-brain barrier penetration. Toxicity profile predictions highlighted potential hepatotoxicity and mutagenicity risks associated with selected lead compounds, emphasizing the importance of further experimental validation and optimization. Overall, this study contributes to the identification and characterization of novel small molecule inhibitors targeting LRRK2 for PD treatment, offering valuable insights into the rational design of potential disease-modifying therapies.