Ligand Based in-silico Study on Pyridopyrimidinedione Derivatives as Dipeptidyl Peptidase-IV Inhibitors

Abstract:

Background: Type-2 diabetes mellitus can be effectively treated with dipeptidyl peptidase- IV inhibitors. Diverse classes of molecules have exhibited promising DPP-IV inhibition. Objective: In this perspective, 3D-QSAR and pharmacophore studies on a series of substituted pyridopyrimidinedione derivatives were performed to explore the structural requirements for effective DPP-IV inhibitory activity. Methods: 3D-QSAR was performed on 3D-QSAR module of Vlife molecular design suite (MDS) while two strategies were used for pharmacophore identification: MolSign module of MDS and Pharmagist. Results: The most significant 3D-QSAR models obtained from kNN and PLSR exhibited 79% and 77% of internal and 66% and 67% of external predictability respectively. The results from both kNN and PLSR models suggest the contribution of electronegative group with optimum bulk to be favourable for biological activity. Additional information about field point S_376 suggests a more bulky group to be favourable around S_376 at R1. The results from pharmacophore studies by both the strategies indicate the contribution of three hydrogen bond acceptors, one hydrogen bond donor and one aromatic feature for biological activity. Conclusion: Findings of the present study can be utilized for development of new lead compounds exhibiting promising DPP-IV inhibitory activity.

Key words: DPP-IV, 3D-QSAR, kNN, Pharmacophore, Pharmagist.