二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究

Study on the Structural Features and Binding Mode of Dihydroisoquinolines as BACE1 Inhibitors

β-分泌酶(BACE1)是水解淀粉样前体蛋白生成β-淀粉样多肽的关键限速酶,近年来已成为治疗阿尔茨海默症的一个理想靶点。本文以34个二氢异喹啉类BACE1抑制剂为研究对象,采用比较分子相似性指数(CoMSIA)法定量研究其结构与生物活性间的构效关系,并建立可靠的3D-QSAR预测模型,运用分子对接法分析其与受体BACE1间的结合模式。结果显示,基于立体场、疏水场和氢键供体场建立的CoMSIA模型稳定性良好、预测能力强(Q^2=0.47,R_(ncv)~2=0.93,R_(pre)~2=0.95)。本研究所得模型和信息较好地解释了二氢异喹啉类BACE1抑制剂的结构特征及其与受体间的结合模式,为后续新型BACE1抑制剂的设计开发提供理论指导。

β-secretase（ BACE1） is responsible for the initial cleavage of transmembrane amyloid precursor protein that leads to the production of β-amyloid（ Aβ） peptides in the brain,and is a prime target for Alzheimer＇s disease（ AD）. In this paper,34 kinds of dihydroisoquinoline derivatives as BACE1 inhibitors were studied by threedimensional quantitative structure-activity relationship and molecular docking methods. The resultant optimal comparative molecular similarity indices analysis（ Co MSIA） model,constructed based on the steric,hydrophobic and hydrogen-bond donor fields,displays a strong predictability（ Q^2= 0. 47,Rncv^2= 0. 93,Rpre^2= 0. 95）. This model and the derived information may help to provide better understanding of the structure features and binding mode of BACE1 inhibitors and to facilitate corresponding novel inhibitors＇ design.