发表机构
Dayananda Sagar University; AIIMS–Bathinda（达亚南达萨加尔大学; 巴廷达印度医学研究理事会阿尤尔维达医学研究所）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究采用多配体同时对接技术筛选出4组优于III期抑制剂的BACE1协同配体组合，为阿尔茨海默病新型联合疗法提供了新方向。
AI 中文摘要
阿尔茨海默病是一种以记忆丧失、认知衰退和行为改变为特征的进行性神经退行性疾病，主要影响老年人。当前治疗方案集中于症状管理，尚无疗法能有效阻止或逆转疾病进展。靶向BACE1（淀粉样斑块形成的关键酶）的新型疗法在临床试验中展现出潜力，但受限于副作用和减缓认知衰退的疗效不足。本研究首次采用多配体同时对接（MLSD）技术，从数千种小分子中筛选潜在的协同抑制剂组合，以期获得优于当前BACE1 III期抑制剂的效果。本研究选取Atabecestat、Elenbecestat、Lanabecestat和Verubecestat等近期III期药物作为对比标准，对具有已知BACE1 IC50值的小分子库进行过滤，标记泛分析干扰（PAINS）化合物和Brenk化合物。单配体对接揭示了配体与蛋白的相互作用，为构建多配体同时对接测试的配体对奠定基础。在这些组合中，CHEMBL4078427与CHEMBL3656158、CHEMBL4078427与CHEMBL3695732、Verubecestat与CHEMBL3656158、CHEMBL4078427与Lanabecestat展现出优异的结合亲和力，分别为-19.90 kcal/mol、-18.45 kcal/mol、-18.07 kcal/mol和-17.67 kcal/mol，显著优于III期抑制剂，且配体间相互作用显示出协同效应。这些发现凸显了MLSD在识别协同化合物相互作用方面的变革潜力，为阿尔茨海默病的新型联合疗法铺平道路。
英文摘要
Alzheimer's disease is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes, primarily affecting the elderly. Current treatments focus on symptom management as no therapies effectively halt or reverse disease progression. Newer therapies targeting BACE1, a key enzyme in amyloid plaque formation, have shown promise in clinical trials, though they have been limited by side effects and insufficient efficacy in slowing cognitive decline. This is the first study where multi-ligand simultaneous docking (MLSD) was employed to identify potential synergistic inhibitor combinations from among thousands of small molecules that could yield better results than the current phase-III inhibitors of BACE1. The recent phase III drugs such as Atabecestat, Elenbecestat, Lanabecestat, and Verubecestat were considered to be standards for comparison in this study. A library of small molecules with known IC50 values against BACE1 was filtered for flagging Pan-Assay Interference (PAINS) and "Brenk" compounds. Single-ligand docking revealed individual ligand interactions with the protein, forming the basis for creating ligand pairs tested in MLSD. Among these combinations, CHEMBL4078427 and CHEMBL3656158, CHEMBL4078427 and CHEMBL3695732, Verubecestat and CHEMBL3656158, and CHEMBL4078427 and Lanabecestat demonstrated excellent binding affinity of -19.90 kcal/mol, -18.45 kcal/mol, -18.07 kcal/mol, and -17.67 kcal/mol with the protein, which is significantly greater than those of phase-III inhibitors, along with inter-ligand interactions indicative of a synergistic effect. These findings underscore the transformative potential of MLSD in identifying synergistic compound interactions, paving the way for novel combination therapies in the treatment of Alzheimer's disease.
Comments\c{opyright} 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License
Journal refAdvanced Neurology 2026, 5(3), 025190052
