Yu Shuling, Yuan Jintao, Zhang Yi, Gao Shufang, Gan Ying, Han Meng, Chen Yuewen, Zhou Qiaoqiao, Shi Jiahua
Key Laboratory of Natural Medicine & Immune-Engineering of Henan Province, Henan University, Kaifeng, 475004, China.
Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
Future Med Chem. 2017 Jun;9(9):847-858. doi: 10.4155/fmc-2017-0002. Epub 2017 Jun 21.
Sodium-glucose cotransporter 2 (SGLT2) is a promising target for diabetes therapy. We aimed to develop computational approaches to identify structural features for more potential SGLT2 inhibitors.
MATERIALS & METHODS: In this work, 46 triazole derivatives as SGLT2 inhibitors were studied using a combination of several approaches, including hologram quantitative structure-activity relationships (HQSAR), topomer comparative molecular field analysis (CoMFA), homology modeling, and molecular docking. HQSAR and topomer CoMFA were used to construct models. Molecular docking was conducted to investigate the interaction of triazole derivatives and homology modeling of SGLT2, as well as to validate the results of the HQSAR and topomer CoMFA models.
The most effective HQSAR and topomer CoMFA models exhibited noncross-validated correlation coefficients of 0.928 and 0.891 for the training set, respectively. External predictions were made successfully on a test set and then compared with previously reported models. The graphical results of HQSAR and topomer CoMFA were proven to be consistent with the binding mode of the inhibitors and SGLT2 from molecular docking.
The models and docking provided important insights into the design of potent inhibitors for SGLT2.
钠-葡萄糖协同转运蛋白2（SGLT2）是糖尿病治疗中一个有前景的靶点。我们旨在开发计算方法以识别更具潜力的SGLT2抑制剂的结构特征。
在本研究中，使用全息定量构效关系（HQSAR）、拓扑异构体比较分子场分析（CoMFA）、同源建模和分子对接等多种方法相结合，对46种作为SGLT2抑制剂的三唑衍生物进行了研究。利用HQSAR和拓扑异构体CoMFA构建模型。进行分子对接以研究三唑衍生物与SGLT2的相互作用及SGLT2的同源建模，并验证HQSAR和拓扑异构体CoMFA模型的结果。
最有效的HQSAR和拓扑异构体CoMFA模型对训练集的非交叉验证相关系数分别为0.928和0.891。在测试集上成功进行了外部预测，然后与先前报道的模型进行了比较。HQSAR和拓扑异构体CoMFA的图形结果被证明与分子对接中抑制剂和SGLT2的结合模式一致。
这些模型和对接为设计强效SGLT2抑制剂提供了重要见解。
