Pharmacokinetics parameters of top 50 compounds.

Alzheimer’s disease (AD) is characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD.阿尔茨海默病（Alzheimer’s disease, AD）以认知功能渐进性衰退、言语障碍及记忆丧失为核心临床特征。其潜在治疗策略可靶向β位淀粉样前体蛋白裂解酶1（beta-site amyloid precursor protein cleavage enzyme 1, BACE1），该酶在淀粉样斑块形成、神经原纤维缠结及过度磷酸化tau蛋白的发生发展过程中发挥关键作用。现有抗阿尔茨海默病药物在安全性、有效性及血脑屏障穿透性方面均存在显著局限性。鉴于此，本研究采用包含415种天然产物的精选化合物库开展BACE1潜在抑制剂的虚拟筛选，该库涵盖不同药用植物来源的萜类、酚类化合物及生物碱。基于对接得分与相互作用分析结果，本研究筛选出50种化合物开展下游分析，包括配体结合相互作用、药代动力学、成药性（druglikeness）及理化参数评估。在先导化合物中，掌叶防己碱（Palmatine，化合物45）与小檗碱（Berberine，化合物49）在排名靠前的化合物中展现出最优的成药性与血脑屏障穿透性。化合物4（2-[(9Z,12Z)-十七碳-9,12-二烯基]-6-羟基苯甲酸）在多数毒性参数中呈无活性状态。药效团分析显示，掌叶防己碱与小檗碱与阳性对照标准化合物具有相似的特征，提示二者具备成为有效抗阿尔茨海默病药物的潜力。进一步的结构化学分析揭示二者共享异喹啉生物碱骨架，阐明了其结构相似性。分子动力学模拟证实，在50 ns生产模拟过程中，掌叶防己碱-BACE1及小檗碱-BACE1复合物均保持良好的结构稳定性。综上，本研究结果表明掌叶防己碱与小檗碱有望成为阿尔茨海默病治疗药物开发及实验验证的潜在候选化合物。