氨基乙内酰脲类BACE1抑制剂的特征结构与作用机制

Structural Features and Interaction Mechanism Exploration of Aminohydantoins as BACE1 Inhibitors

对BACE1抑制剂的研究与开发已成为目前治疗阿尔兹海默症的主要研究方向之一。本文选取105个氨基乙内酰脲类BACE1抑制剂作为研究对象,借助比较分子相似性指数(Comparative Molecular Similarity Index,CoMSIA)和分子对接方法建立定量构效关系预测模型,研究影响化合物抑制活性的特征结构信息,揭示该类抑制剂与靶标之间的作用模式。结果表明,模型具有较强的预测能力(Q^2=0.45,R^2ncv=0.87,R^2pre=0.85),抑制剂主要占据了靶标的S3、S1和S2′位点,其主要作用力类型为氢键力。实验所得模型和信息可为日后研究开发新型高效的BACE1抑制剂提供一定的理论指导,节省研究时间与费用。

The research and development of BACE1 inhibitor has become one of the main research directions in the treatment of Alzheimer’s disease(AD).In this study,105 aminohydantoins BACE1 inhibitors were selected as research objects.By virtue of Comparative Molecular Similarity Index(CoMSIA)and molecular docking method,a prediction model of quantitative structure-activity relationship was established to study the structural feature information that influences the inhibitory activity of compounds and reveal the mode of action between these inhibitors and targets.The results showed that the model possesses a strong prediction ability(Q^2=0.45,R^2ncv=0.87,R^2pre=0.85),and the inhibitors mainly occupy the S3,S1 and S2′active sites of target through the hydrogen bond force.The model and information obtained from the experiment can provide theoretical guidance for the development of new and effective BACE1 inhibitors.