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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。
DPP4 is one of the important drug target enzymes for the treatment of type 2 diabetes. There are a number of DPP4 inhibitor drug molecules that are on the market or undergoing clinical trials where sitagliptin has been widely used. 3D-QSAR study of sitagliptin and its derivatives was conducted in order to further study the characteristics of drug molecules resistant to type 2 diabetes and to design new drug molecules. The 3D-QSAR model in this paper is constructed by a training set of 38 molecules including sitagliptin, and the predictive power of the model is tested with 16 derivative molecules. The results show that the correlation coefficients between the calculated and measured values obtained by CoMFA (comparative molecular force field method) and the test set are 0.921 and 0.884, respectively. Using the spatial and charge profiles derived from CoMFA as a basis for DPP4 inhibitor design and structural improvement, we designed a new, more active inhibitor molecule. Therefore, the molecular docking of DPP4 inhibitors with drug target enzymes and their 3D-QSAR studies will help us understand the mechanism of drug molecule binding to DPP4 and design new drug molecules.