Abstract
Spinocerebellar Ataxia Type 1 (SCA1) is a progressive neurodegenerative disorder caused by the expansion and aggregation of polyglutamine (polyQ) in the Ataxin-1 (ATXN1) protein, leading to severe neuronal dysfunction. Currently, only symptomatic treatments are available, highlighting the requirement for disease-modifying therapies. This study employed a detailed in silico approach to identify potential neuroprotective natural compounds targeting the Ataxin-1 protein implicated in SCA1. The three-dimensional structure of Ataxin-1 was retrieved, validated, and optimized to achieve a stable structural model. Validation using a Ramachandran plot indicated that 77% of the residues were in favored regions, confirming the reliability of the protein structure. Active site residues were identified using CASTp, and receptor grids were generated for molecular docking studies. A library of 50 natural compounds was screened, among which 21 satisfied Lipinski's rule of five. Molecular docking using PyRx and AutoDock 4.2 identified Withanolide A as the top candidate, exhibiting the highest binding affinity (- 10.14 kcal/mol) and forming four hydrogen bonds with key active site residues. The top six ligands were further assessed for ADMET properties, with Withanolide A showing optimal drug-likeness, high gastrointestinal and blood-brain absorption, and non-toxic profiles. Molecular dynamics simulations over 200 ns demonstrated the stability of the Ataxin-1-Withanolide A complex, supported by RMSD, RMSF, RoG, and SASA analyses. PCA revealed reduced conformational flexibility, indicating enhanced structural stability of the ligand-bound complex. Additionally, MM-PBSA analysis confirmed that Van der Waals interactions were the primary stabilizing forces, complemented by electrostatic contributions. This integrated computational approach highlights the therapeutic potential of Withanolide A as a neuroprotective agent for SCA1, providing a base for future experimental validation and drug development.