Niño Helena, García-Pintos Isela, Rodríguez-Borges José E, Escobar-Cubiella Manolo, García-Mera Xerardo, Prado-Prado Francisco
Department of Organic Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain.
Curr Comput Aided Drug Des. 2011 Dec;7(4):263-75. doi: 10.2174/157340911798260322.
Alzheimer's disease (AD) is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide, are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE-1 enzyme is essential for the generation of β-amyloid. BACE-1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies, including neuronal loss and certain memory deficits. The fact that BACE-1 initiates the formation of β-amyloid, and the observation that BACE-1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE-1 inhibition, thus reducing β-amyloid and its associated toxicities. In this sense, quantitative structure-activity relationships (QSAR) could play an important role in studying these β-secretase inhibitors. QSAR models are necessary in order to guide the β-secretase synthesis. This work is aimed at reviewing different design and synthesis and computational studies for a very large and heterogeneous series of β-secretase inhibitors. First, we review design, synthesis, and Biological assay of β-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compounds to find out the structural requirements. Next, we review QSAR studies using the method of Linear Discriminant Analysis (LDA) in order to understand the essential structural requirement for receptor binding for β- secretase inhibitors.
阿尔茨海默病（AD）极为复杂。尽管该疾病具有多种病理特征，但由β-淀粉样肽组成的淀粉样斑块是阿尔茨海默病大脑中的标志性神经病理病变。确实，大量证据表明β-淀粉样蛋白是AD病理生理学的核心，并且可能在这种难治性神经退行性疾病中起早期作用。β-分泌酶1（BACE-1）酶对于β-淀粉样蛋白的产生至关重要。BACE-1基因敲除小鼠不产生β-淀粉样蛋白，并且没有与阿尔茨海默病相关的病理特征，包括神经元丢失和某些记忆缺陷。BACE-1启动β-淀粉样蛋白的形成这一事实，以及在该疾病中BACE-1水平升高的观察结果，为开发针对BACE-1抑制的疗法提供了直接且令人信服的理由，从而减少β-淀粉样蛋白及其相关毒性。从这个意义上讲，定量构效关系（QSAR）在研究这些β-分泌酶抑制剂方面可以发挥重要作用。为了指导β-分泌酶的合成，QSAR模型是必要的。这项工作旨在综述针对非常大量且种类繁多的β-分泌酶抑制剂的不同设计、合成及计算研究。首先，我们综述β-分泌酶抑制剂的设计、合成及生物学测定。接下来，我们综述二维QSAR、三维QSAR、比较分子场分析（CoMFA）、比较分子相似性指数分析（CoMSIA）以及与不同化合物的对接，以找出结构要求。接下来，我们综述使用线性判别分析（LDA）方法的QSAR研究，以便了解β-分泌酶抑制剂与受体结合的基本结构要求。
