Anjum Farah, Hawsawi Nahed, Almalki Abdulraheem Ali, Shamsi Anas, Hulbah Maram Jameel, Bakhuraysah Maha, Alsharif Abdulaziz, Mohammad Taj
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
King Salman Center for Disability Research, Riyadh, Saudi Arabia.
Front Pharmacol. 2025 Sep 4;16:1661744. doi: 10.3389/fphar.2025.1661744. eCollection 2025.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that results in the degeneration of motor neurons and is typically linked to toxic aggregates of mutant superoxide dismutase 1 (SOD1) protein. As autophagy is critical for the removal of these toxic protein aggregates, stimulating autophagy has emerged as a promising therapeutic approach for ALS. Unc-51-like kinase 1 (ULK1) is a key regulator of autophagy and has been shown to have the potential to prevent ALS pathology when activated. However, synthetic ULK1 activators are frequently limited by toxicity and suboptimal pharmacokinetic profiles. This study aimed to identify natural ULK1 activators using a systematic virtual screening approach for potential ALS therapy.
This study employed a comprehensive virtual screening approach to identify phytochemicals capable of activating ULK1. Natural compounds from the IMPPAT database were screened using molecular docking, followed by pan-assay interference compounds (PAINS) filtering, pharmacokinetic profiling, and density functional theory (DFT) analysis. Further, biological activity was predicted using the PASS tool, and candidate molecules were subjected to molecular dynamics (MD) simulations, essential dynamics, and binding free energy calculations via MM-PBSA.
The systematic screening in this study identified Candidine and Delavinone as high-affinity binders with reference to BL-918, proposing them as potential activators of ULK1. Both compounds demonstrated favorable drug-likeness, stable interactions with ULK1 in MD simulations, and promising ALS-relevant activity profiles. Essential dynamics and MM-PBSA further supported the binding stability and energetic favorability of these interactions.
Candidine and Delavinone emerge as promising phytochemical activators of ULK1 with potential therapeutic relevance for ALS. These findings warrant further experimental validation and preclinical studies to explore their efficacy in autophagy modulation and neuroprotection.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，会导致运动神经元退化，通常与突变型超氧化物歧化酶1（SOD1）蛋白的毒性聚集体有关。由于自噬对于清除这些有毒蛋白质聚集体至关重要，刺激自噬已成为一种有前景的ALS治疗方法。Unc-51样激酶1（ULK1）是自噬的关键调节因子，已证明其激活后有预防ALS病理的潜力。然而，合成的ULK1激活剂常常受到毒性和不理想的药代动力学特征的限制。本研究旨在使用系统虚拟筛选方法来识别天然的ULK1激活剂，用于潜在的ALS治疗。
本研究采用全面的虚拟筛选方法来识别能够激活ULK1的植物化学物质。使用分子对接对IMPPAT数据库中的天然化合物进行筛选，随后进行泛测定干扰化合物（PAINS）过滤、药代动力学分析和密度泛函理论（DFT）分析。此外，使用PASS工具预测生物活性，并通过MM-PBSA对候选分子进行分子动力学（MD）模拟、主成分动力学分析和结合自由能计算。
本研究中的系统筛选确定了念珠碱和脱氢紫堇碱是相对于BL-918的高亲和力结合剂，表明它们是ULK1的潜在激活剂。两种化合物均表现出良好的类药性质，在MD模拟中与ULK1有稳定的相互作用，以及有前景的与ALS相关的活性特征。主成分动力学分析和MM-PBSA进一步支持了这些相互作用的结合稳定性和能量有利性。
念珠碱和脱氢紫堇碱成为有前景的ULK1植物化学激活剂，对ALS具有潜在的治疗相关性。这些发现需要进一步的实验验证和临床前研究，以探索它们在自噬调节和神经保护方面的疗效。
