中文摘要：

DPP4是一种治疗Ⅱ型糖尿病的重要药物靶标酶之一。已有多种上市或者正在进行临床试验的DPP4抑制剂药物分子,其中西他列汀（sitagliptin）已被广泛使用。为了进一步研究抗Ⅱ型糖尿病药物分子的特性并设计新的药物分子,对西他列汀及其衍生物进行了3D-QSAR研究。文中的3D-QSAR模型由38个包括西他列汀在内分子的训练集所构建,所建模型的预报能力用16个衍生物分子进行测试。结果表明,采用CoMFA（比较分子力场法）所得活性计算值和实测值对于训练集和测试集的相关系数平方分别为0.921和0.884。以CoMFA得出的空间和电荷分布图作为DPP4抑制剂分子设计和结构改进的依据,我们设计了新的具有更高活性的抑制剂分子。因此,通过对DPP4抑制剂与药物靶标酶的分子对接及其3D-QSAR研究,有助于我们深入了解药物分子和DPP4的结合作用机理,进而设计新的药物分子。

英文摘要：

Dipeptidyl peptidaseⅣ（DPP4）is a validated target protein for the treatment of typeⅡdiabetes.There are several DPP4 inhibitor drugs already launched or under clinical trial.In order to investigate the characteristics of the drugs and design new inhibitors,3D-QSAR study was conducted among sitagliptin and its derivates for the drug target of DPP4.In this work,pIC_（50）（the negative logarithm of IC_（50））was used as the biological activity.The 3D-QSAR model was generated by the training set composed of 38 molecules including sitagliptin and validated by the test set composed of 16 molecules.The CoMFA（Comparative Molecular Field Analysis）model was developed by steric and electrostatic field methods. Based on the model constructed,the squares of correlation coefficients between the calculated and experimental activities for the training set and test set are 0.921,0.884 respectively.Analysis of CoMFA contour map which consisted of steric and electrostatic field effects gave a significant insight to the factors responding for the structural requirements of inhibitors.It was concluded that the CoMFA model could be used to design new inhibitors with higher activity.Besides,molecular docking of newly designed molecule to inhibit DPP4 was helpful in exploring the binding mechanisms in detail.