Bhattacharya Soham, Gupta Neha, Dutta Adrish, Khanra Pijush Kanti, Dutta Ritesh, Žiarovská Jana, Tzvetkov Nikolay T, Severová Lucie, Kopecká Lenka, Milella Luigi, Fernández-Cusimamani Eloy
Department of Agroecology and Crop Production, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague, Prague, Czechia.
Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences Prague, Prague, Czechia.
Front Pharmacol. 2025 Apr 16;16:1519145. doi: 10.3389/fphar.2025.1519145. eCollection 2025.
Neurodegenerative disorders (NDs) are typically characterized by progressive loss of neuronal function and the deposition of misfolded proteins in the brain and peripheral organs. They are molecularly classified based on the specific proteins involved, underscoring the critical role of protein-processing systems in their pathogenesis. Alpha-synuclein (α-syn) is a neural protein that is crucial in initiating and progressing various NDs by directly or indirectly regulating other ND-associated proteins. Therefore, reducing the α-syn aggregation can be an excellent option for combating ND initiation and progression. This study presents an phytochemical-based approach for discovering novel neuroprotective agents from bioactive compounds of the Lamiaceae family, highlighting the potential of computational methods such as functional networking, pathway enrichment analysis, molecular docking, and simulation in therapeutic discovery. Functional network and enrichment pathway analysis established the direct or indirect involvement of α-syn in various NDs. Furthermore, molecular docking interaction and simulation studies were conducted to screen 85 major bioactive compounds of the Lamiaceae family against the α-syn aggregation. The results showed that five compounds (α-copaene, γ-eudesmol, carnosol, cedryl acetate, and spathulenol) had a high binding affinity towards α-syn with potential inhibitory activity towards its aggregation. MD simulations validated the stability of the molecular interactions determined by molecular docking. In addition, pharmacokinetic analysis underscores their potential as promising drug candidates, demonstrating excellent blood-brain barrier (BBB) permeability, bioactivity, and reduced toxicity. In summary, this study identifies the most suitable compounds for targeting the α-syn aggregation and recommends these compounds as potential therapeutic agents against various NDs, pending further and validation.
神经退行性疾病（NDs）的典型特征是神经元功能进行性丧失以及错误折叠蛋白在大脑和外周器官中的沉积。它们根据所涉及的特定蛋白质进行分子分类，突出了蛋白质加工系统在其发病机制中的关键作用。α-突触核蛋白（α-syn）是一种神经蛋白，通过直接或间接调节其他与ND相关的蛋白质，在各种ND的发生和发展中起关键作用。因此，减少α-syn聚集可能是对抗ND发生和发展的一个极佳选择。本研究提出了一种基于植物化学的方法，用于从唇形科植物的生物活性化合物中发现新型神经保护剂，强调了功能网络、通路富集分析、分子对接和模拟等计算方法在治疗发现中的潜力。功能网络和富集通路分析确定了α-syn在各种ND中的直接或间接参与。此外，进行了分子对接相互作用和模拟研究，以筛选唇形科植物的85种主要生物活性化合物对α-syn聚集的影响。结果表明，五种化合物（α-可巴烯、γ-桉叶醇、鼠尾草酚、乙酸雪松酯和匙叶桉油烯醇）对α-syn具有高结合亲和力，并对其聚集具有潜在抑制活性。分子动力学（MD）模拟验证了分子对接所确定的分子相互作用的稳定性。此外，药代动力学分析强调了它们作为有前景的药物候选物的潜力，显示出优异的血脑屏障（BBB）通透性、生物活性和降低的毒性。总之，本研究确定了针对α-syn聚集最合适的化合物，并推荐这些化合物作为针对各种ND的潜在治疗剂，但有待进一步研究和验证。
