Virtual Screening-Based Discovery of Potent Hypoglycemic Agents: In Silico, Chemical Synthesis and Biological Study

Abstract

Background: Dipeptidyl peptidase IV has been reported to be an important target for the development and discovery of new therapies for diabetes mellitus type II.

Objective: The main aim of this study was to discover chemical entities that target the inhibition of DPP IV and feature potent hypoglycemic action.

Methods: A structure-based virtual screening was applied to discover new hypoglycemic agents. Molecular docking was performed to compute the binding free energies. Molecular dynamics simulations were done to evaluate the binding stability of resulted hits.

Results: Seven small non-peptide potential inhibitors of Dipeptidyl peptidase IV with 3-imino-4-(4- substituted phenyl)-1, 2, 5-thiadiazolidine-1,1-dioxide scaffold were discovered. The binding free energies ranged from -24.50 to -36.06 kJ/mol. Molecular dynamics simulations revealed high stability of all protein-ligand complexes with low root mean square deviation over 10 ns simulation time. The tested compounds expressed a significant reduction in blood glucose level up to 90% with excellent oral glucose tolerance test after 120 minutes of injection in a diabetes mellitus type II animal model. A promising release of insulin was observed with a potential hypoglycemic activity for all compounds.

Conclusion: The virtual screening was successful to discover potent hypoglycemic agents with drug-like properties that may need more consideration for future studies and development.

Keywords: Virtual screening; diabetes type II; dipeptidyl peptidase IV; docking; hypoglycemic action; molecular dynamics.