β-secretase (BACE-1) is a potential target for the treatment of Alzheimer's disease (AD). Despite its potential, only few compounds targeting BACE have entered the clinical trials. Herein, we describe the identification of Gefitinib as a potential lead compound for BACE through an integrated approach of structural bioinformatics analysis, experimental assessment and computational analysis. In particular, we performed ELISA and western analysis to assess the effect of Gefitinib using N2a human APP695 cells. In addition, we investigated the binding mechanism of Gefitinib with BACE through molecular docking coupled with molecular dynamics simulations. The computational analyses revealed that hydrophobic contact is a major contributing factor to the binding of Gefitinib with BACE. The results obtained in the study have rendered Gefitinib as a putative lead compound for BACE. Further optimization studies are warranted to improve its potency and pharmacological properties against BACE for potential AD treatment.

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基于结构生物信息学的EGFR抑制剂吉非替尼作为BACE公认的先导化合物的鉴定。

β-分泌酶（BACE-1）是治疗阿尔茨海默氏病（AD）的潜在靶标。尽管具有潜力，但靶向BACE的化合物很少进入临床试验。本文中，我们通过结构生物信息学分析，实验评估和计算分析的集成方法，描述了吉非替尼作为BACE的潜在先导化合物的鉴定。特别是，我们使用N2a人APP695细胞进行了ELISA和Western分析，以评估吉非替尼的作用。此外，我们通过分子对接和分子动力学模拟研究了吉非替尼与BACE的结合机理。计算分析表明，疏水性接触是吉非替尼与BACE结合的主要因素。研究获得的结果使吉非替尼成为BACE的公认先导化合物。必须进行进一步的优化研究，以提高其针对BACE的潜在AD治疗的效力和药理特性。