Drug likeness prediction by DruLito software.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, driven by the accumulation of amyloid-beta plaques and neurofibrillary tangles. It involves the dysfunction of key enzymes such as Acetylcholinesterase (AChE) and β-secretase (BACE1), making them critical targets for therapeutic intervention. In this study we investigated an in-house library of 820 secondary metabolites obtained from Ayurvedic plants against AChE and BACE1 with the aim to discover novel leads for AD. Virtual screening resulted in 15 ligands, mostly belonging to the ursane-type or dammarene-type triterpene saponins of Centella asiatica, reestablishing the potency of this plant in drug discovery against AD. The binding affinities were further verified by molecular dynamics (MD) simulation trajectories, including root mean square fluctuations (RMSF), root mean square deviation (RMSD), hydrogen bonding analysis, Coulomb interaction calculation, Lennard-Jones interactions, and the total interaction energy. Moreover, extensive Principal Component Analysis (PCA) and Gibbs free energy landscape were performed. Our results demonstrated three compounds, namely (S)-eriodictyol 7-O-(6-β-O-trans-p-coumaroyl)-β-d-glucopyranoside, sitoindoside-X and 1,5-di-o-caffeoyl quinic acid as more effective in treating AD due to their comparable drug-like properties. Drug-likeness, structural chemistry, pharmacophore, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis support their potential for future drug development. To establish the effectiveness of these lead compounds against AD, additional experimental testing should be performed.

阿尔茨海默病（Alzheimer’s disease, AD）是一类以认知功能减退为核心特征的神经退行性疾病，其发病与β-淀粉样蛋白斑块及神经原纤维缠结的异常堆积密切相关。该疾病伴随乙酰胆碱酯酶（Acetylcholinesterase, AChE）与β-分泌酶（β-secretase, BACE1）等关键酶的功能异常，二者因此成为抗AD治疗的重要干预靶点。本研究构建了一套源自阿育吠陀（Ayurvedic）药用植物的820种次生代谢物自建库，针对AChE与BACE1开展筛选，以期发现抗阿尔茨海默病的新型先导化合物。经虚拟筛选共获得15个活性配体，其中多数为积雪草（Centella asiatica）中的齐墩果烷型（ursane-type）或达玛烯型（dammarene-type）三萜皂苷，再次证实了该植物在抗AD药物研发中的应用潜力。后续通过分子动力学（molecular dynamics, MD）模拟轨迹对候选配体的结合亲和力进行了验证，分析维度涵盖均方根波动（root mean square fluctuations, RMSF）、均方根偏差（root mean square deviation, RMSD）、氢键相互作用分析、库仑相互作用计算、伦纳德-琼斯（Lennard-Jones）相互作用分析以及总相互作用能测算。此外还开展了全面的主成分分析（Principal Component Analysis, PCA）与吉布斯自由能景观分析。研究结果表明，(S)-圣草酚7-O-(6-β-O-反式-对香豆酰基)-β-d-吡喃葡萄糖苷、sitindoside-X以及1,5-二咖啡酰奎宁酸这三种化合物展现出更优异的抗AD活性，其类药性质与现有候选化合物相当。类药性、结构化学、药效团以及ADMET（吸收、分布、代谢、排泄与毒性）分析均支持这三种化合物具备后续药物开发的潜在价值。为进一步验证这些先导化合物的抗AD有效性，仍需开展后续的实验测试。