MOLECULAR MODELING STUDY OF SOME DIPEPTIDYL PEPTIDASE IV (DPP-IV) INHIBITORS AS ANTIDIABETIC AGENTS

Steffy Mary Chandy*, Sudha Vengurlekar and S. C. Chaturvedi

ABSTRACT

Type II diabetes is establishing itself as an epidemic of the 21st century and is a severe and increasingly prevalent disease. The present study successfully applied pharmacophore mapping, 3D-QSAR and molecular docking analysis to characterize a set of synthesized DPP-IV inhibitors. The selected series of imidazoquinoline derivatives included 47 compounds out of which 38 compounds were put in training set and remaining 9 compound were put in test set on the basis of diversity using the SYBYL X 2.1.1 software. The pharmacophore models were derived using GALAHAD module of SYBYL X 2.1.1 software. The optimal pharmacophore model contains nine pharmacophore features. The models include four hydrophobes, three hydrogen bond acceptors and two positive nitrogen centres. Successful CoMFA models were generated from imidazoquinoline derivatives which displayed a cross-validated correlation coefficient (Q2) of 0.526 and a non-cross related coefficient (R2) of 0.946. Moreover the contour maps derived from CoMFA models provided enough information to understand the SAR and to identify the structural features influencing DPP-IV inhibitory activity. The docking studies of the eight designed compounds were performed using the SURFLEX DOCK module of SYBYL X 2.1.1 software. The binding mode of designed compounds at the active site of DPP-IV enzyme (PDB ID. 4DSA) was explored and hydrogen-bonding interactions were observed between the inhibitor and the target.

Keywords: Type II diabetes, DPP-IV inhibitors, SYBYL X 2.1.1 software, GALAHAD, SURFLEX DOCK, imidazoquinoline derivatives.