Title:Virtual Screening-Based Discovery of Potent Hypoglycemic Agents: In Silico, Chemical Synthesis and Biological Study
VOLUME: 16 ISSUE: 6
Author(s):Mohammed A. Khedr *, Omar M. M. Mohafez and Ibrahim A. Al-Haider
Affiliation:Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa
Keywords:Virtual screening, diabetes type II, docking, dipeptidyl peptidase IV, molecular dynamics, hypoglycemic action.
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.
