Title:De Novo Design of High Potent DPP-IV Inhibitors Based on the Scaffold of Cyanopyrrolidine
Volume: 12
Issue: 6
Author(s): Yu-Lei Jiang, Hao-Liang Yuan, Wei-Wei Zhang, Hai-Chun Liu, Yan-Min Zhang, Xiao Xiong, Jin-Xing Xu, Shuai Lu, Tao Lu and Ya-Dong Chen
Affiliation:
Keywords:
DPP-IV, 3D-QSAR, pharmacophore, fragment, type 2 diabetes.
Abstract: Dipeptidyl peptidase IV (DPP-IV) is an attractive target, and its launched inhibitors have
made great significance to clinical therapy of type 2 diabetes. For developing high potent DPP-IV inhibitors,
ligand- and structure-based approaches were applied for the optimization of cyanopyrrolidine in this study. Two
statistically significant 3D-QSAR models (CoMFA with q2, 0.585; r2, 0.963; CoMSIA with q2, 0.678; r2, 0.949) were developed.
In combination with the structure-based pharmacophore model, fundamental structural requirements and pharmacophoric
features for R groups were determined. Suitable fragments for different R groups were retrieved for the generation
of novel molecules. After being evaluated by molecular docking, QuaSAR descriptors filter and 3D-QSAR activity
prediction, active DPP-IV inhibitors were found. The reliability indicated this workflow can be applied to facilitate
lead optimization for DPP-IV and even for other drug targets.