3D-QSAR studies of dipeptidyl peptidase-4 inhibitors using various alignment methods

Abstract

Dipeptidyl peptidase-4 (DPP-4) is one of the most attractive targets in the area of type 2 diabetes treatment. Till date, many structurally diverse DPP-4 inhibitors have been explored and published. To identify essential structural features of these diverse DPP-4 inhibitors responsible for antidiabetic activity, three-dimensional quantitative structure–activity relationship analyses were carried out on 36 reported quinoline and isoquinoline derivatives. The studies include comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) using three different alignment methods. The distill rigid body alignment-based CoMFA and CoMSIA models gave best significant results for 27 training set molecules, with cross-validated coefficients (q2) of 0.803 and 0.826, respectively, and conventional coefficients (r2) of 0.991 and 0.983, respectively. Validation by test set of nine molecules gave excellent predicted correlation coefficients (rpred 2 ) of 0.874 and 0.847 for CoMFA and CoMSIA models, respectively. Detailed analysis of CoMFA and CoMSIA contour maps revealed many helpful structural insights to improve the activity of newly designed quinoline and isoquinoline derivatives as DPP-4 inhibitors for the treatment of type-2 diabetes.