Background: Dipeptidyl peptidase-4 (DPP4), a serine exopeptidase which is
found in human, is encoded by the DPP4 gene. Glucagon-like peptide-1 (GLP-1) and gastric
inhibitory polypeptide (GIP) levels increase in the presence of DPP-4 inhibitors,
which also inhibit the release of glucagon. Accordingly, insulin secretion increases with
gastric emptying and blood glucose levels decrease.
Objective: The aim of the present work was to screen suitable DPP4 inhibitors which can
be used to treat diabetes mellitus type 2.
Method: 230 sulfonyl-benzamides have been screened by Discovery Studio Molecular
Docking Programme to search the best suitable molecule for type 2 diabetes treatment. To
find inhibitors with high stability and flexibility, molecular dynamics (MD) simulation
has been done and Lipinski’s rule of five protocols has been employed to screen druglikeness.
ADMET (absorption, distribution, metabolism, excretion and toxicity) filtration
has also been used to value the toxicity. Among them, 106 sulfonyl-benzamide showed
better docking score than the approved diabetes mellitus type 2 drug. These sulfonylbenzamides
also passed the ADMET and druglikeness filters. Quantitative structure–
activity relationship has been studied to observe change in the docking properties with the
change of druglike sulfonyl-benzamide molecules. DFT computation of optimized geometry
and derivation of molecular orbitals have been used to correlate the druglikeness.
The small difference in the energy between HOMO and LUMO may help to activate the
drug in the protein environment quickly. Pharmacophore generation has been done to
recognize the inhibitors binding modes in the active site of receptor.
(MSPB) showed the best theoretical efficiency as DPP-4 inhibitor.
Conclusion: Structure based drug design approach for the treatment of type-2 diabetes
revealed its influence on the development of new DPP-4 sulfonyl-benzamide inhibitors.