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Review Article

阿尔茨海默病和 β-分泌酶抑制：以计算机辅助抑制剂设计为重点的更新

卷 23, 期 3, 2022

发表于: 09 August, 2021

页: [266 - 285] 页: 20

弟呕挨: 10.2174/1389450122666210809100050

价格: $65

摘要

简介：阿尔茨海默病 (AD) 由于其不可逆转的性质，是一种加剧的神经退行性疾病。 β 位点淀粉样前体蛋白 (APP) 裂解酶 1 (BACE1) 的鉴定一直是 AD 治疗的重要医学焦点，这为几项研究开辟了基础。尽管在这个方向上进行了许多工作，但没有 BACE1 抑制剂作为抗 AD 药物进入最终批准阶段。 方法：我们提供主题的介绍性背景以及 AD 发病机制的一般概述。该审查以 BACE1 抑制剂的设计和开发为特色，重点关注一些临床试验和停产药物。使用 Web of Science 和 Scopus 数据库中的主题关键词 BACE1、抑制剂设计和计算/理论研究，我们检索了超过 49 篇相关文章。搜索年份为 2010 年和 2020 年，分析时间为 2020 年 5 月至 2021 年 3 月。 结果和讨论：研究人员采用计算方法来解开潜在的 BACE1 抑制剂，并取得显着成果。在 BACE1 抑制剂设计和结合/相互作用研究中最常用的计算机辅助方法是药效团开发、定量构效关系 (QSAR)、虚拟筛选、对接和分子动力学 (MD) 模拟。这些方法，加上更先进的方法，包括量子力学/分子力学 (QM/MM) 和 QM，已在 BACE1 抑制剂设计的计算框架中证明是重要的。计算化学家已经接受了体外试验的结合，以深入了解已识别分子的抑制性能，这些分子具有对 BACE1 的潜在抑制作用。文献中提供了高达 50 nM 的显着 IC50 值，优于临床试验化合物。 结论：强效 BACE1 抑制剂在临床试验中的持续失败吸引了许多质疑，促使研究人员研究有效抑制剂设计所必需的新概念。高效 BACE1 抑制剂设计所考虑的特性似乎是巨大的，需要彻底审查。最近，研究人员注意到，除了明显的结合亲和力和血脑屏障 (BBB) 渗透外，BACE1 抑制剂对渗透性糖蛋白的亲和力必须很低或没有。计算建模方法在药物发现策略中有着深远的应用。随着最近关于 BACE1 抑制的计算机研究的数量，识别将达到批准水平的有效分子的前景是可行的。研究人员应尝试将许多已鉴定的具有显着抗 AD 特性的 BACE1 化合物推向临床前和临床试验阶段。我们还建议对 BACE1 的变构抑制剂设计、外部建模和多位点抑制进行计算研究。这些替代方案可能是 AD 治疗中 BACE1 药物发现的解决方案。

关键词: β-分泌酶、阿尔茨海默病 (AD)、BACE1 抑制、抗 AD 药物、计算机辅助抑制剂设计、对接

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