葡萄糖激酶激动剂药效团模型的构建及应用  

Construction and application of 3D-pharmacophore model of glucokinase agonists

作　　者：唐春雷[1,2] 黄文龙[1] 钱海[1] 

机构地区：[1]中国药科大学新药研究中心,南京210009 [2]江南大学药学院,无锡214122

出　　处：《中国药科大学学报》2015年第2期181-187,共7页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.30772647;No.81001363;No.21305051)~~

摘　　要：葡萄糖激酶（GK）在调节碳水化合物代谢过程中起着重要的作用,已成为2型糖尿病药物研究的热门靶点之一。本研究选取了25个生物活性跨度达5个数量级（2~78 000 nmol/L）的GK激动剂作为训练集,利用Discovery studio2.5软件中的3D-QSAR Pharmacophore Generation模块构建GK激动剂药效团模型。构建得到的药效团模型具有3个氢键受体、1个疏水中心和3个排除体积,相关性系数为0.955,Δcost为60.5,标准偏差为0.714。药效团模型经训练集验证、测试集验证、Fischer验证和筛选能力验证。本研究利用所构建的药效团模型对本课题组合成的穿心莲内酯衍生物库进行虚拟筛选,得到了具有潜在GK激动活性的小分子,初步的药理活性评价验证药效团模型具备较好的筛选能力。Glucokinase （GK）, which plays a pivotal role in maintaining glucose equilibrium in the human body, emerged as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of glucokinase agonist inhibitors have been generated with a training set of 25 glucokinase agonists （ EC50 values from 2 to 78 000 nmol/L） using Discovery studio 2.5. The best hypothesis contained three hydrogen bond acceptors, one hydrophobic center, and three excluded volumes with a correlation coefficient of 0. 955, cost difference of 60. 5, RMSD of 0. 714. This model was validated by test set, Fischer randomization test and decoy set methods. Pharmacophore model was also utilized as a three dimentional query to screen in-house andrographolide derivative database. New potential GK agonist was obtained therewith, and the hit compound is capable for further screening assay studies. Preliminary biological evaluation suggests that this new pharmacophore model fuctions superiorly in virtual screening.

关 键 词：葡萄糖激酶 药效团模型 穿心莲内酯衍生物 虚拟筛选 

分 类 号：R91[医药卫生—药学]