Singh Surbhi, Singh Suchitra, Joshi Deepika, Mohanty C, Singh Royana
Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh India.
Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh India.
In Silico Pharmacol. 2025 Mar 15;13(1):46. doi: 10.1007/s40203-025-00308-6. eCollection 2025.
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.
1型脊髓小脑共济失调（SCA1）是一种进行性神经退行性疾病，由Ataxin-1（ATXN1）蛋白中多聚谷氨酰胺（polyQ）的扩增和聚集引起，导致严重的神经元功能障碍。目前，只有对症治疗方法，这凸显了对疾病修饰疗法的需求。本研究采用详细的计算机模拟方法，以鉴定针对与SCA1相关的Ataxin-1蛋白的潜在神经保护天然化合物。检索、验证并优化了Ataxin-1的三维结构，以获得稳定的结构模型。使用拉氏图进行验证表明，77%的残基位于有利区域，证实了蛋白质结构的可靠性。使用CASTp鉴定活性位点残基，并生成受体网格用于分子对接研究。筛选了一个包含50种天然化合物的文库，其中21种符合Lipinski的五规则。使用PyRx和AutoDock 4.2进行分子对接，确定Withanolide A为最佳候选物，表现出最高的结合亲和力（-10.14 kcal/mol），并与关键活性位点残基形成四个氢键。对排名前六位的配体进一步评估其ADMET特性，Withanolide A显示出最佳的类药性质、高胃肠道和血脑吸收以及无毒特性。超过200 ns的分子动力学模拟证明了Ataxin-1-Withanolide A复合物的稳定性，RMSD、RMSF、RoG和SASA分析支持了这一点。主成分分析显示构象灵活性降低，表明配体结合复合物的结构稳定性增强。此外，MM-PBSA分析证实范德华相互作用是主要的稳定力，静电作用起辅助作用。这种综合计算方法突出了Withanolide A作为SCA1神经保护剂的治疗潜力，为未来的实验验证和药物开发奠定了基础。
