β分泌酶抑制剂的药效团模型研究

Pharmacophore Model Construction of β-Secretase Inhibitors

选择活性跨越0.002至25μmol·L-1的4类共25个β分泌酶抑制剂作为训练集,使用Catalyst软件包构建出药效团模型,并通过对药效团的有效性分析,筛选得到的最佳模型(Correl=0.969,Config=16.32,Δcost=62.422)由一个环芳香性、一个疏水中心、一个正电荷中心和一个氢键供体组成.并用其它209个抑制剂组成测试集对模型进行验证,结果表明该模型显示出较强的预测能力,能够为进一步的数据库搜索,寻找新型的β分泌酶抑制剂先导物提供依据。

Pharmacophore models of β-secretase inhibitors were developed by using Catalyst HypoGen program with a training set of 25 compounds （IC50 values from 0.002 to 25 μmol·L^-1） containing 4 different kinds of structures. A fitting pharmacophore hypothesis （Correl= 0.969, Config= 16.32, Acost= 62.422） was characterized by one aromatic ring center, one aliphatic hydrophobic core, one positive ionizable center and one hydrogen bond donor. The model was applied to predicting the activity of other 209 inhibitors as a test set. The result indicates that the pharmacophore model exhibits good predictive ability and is able to provide clear guidelines for screening new lead compounds of β-secretase inhibitors.