Dipeptidyl peptidase-4 (
DPP4) inhibitors are a potent therapeutic treatment for
type 2 diabetes mellitus (T2DM). There is a family of compounds used as
DPP4 inhibitors (DPP4Is) called
gliptins. They bind tightly to DPP4 to form an inactive
protein-
ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of
gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with
gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used
gliptins. The newly identified compounds interacted with the dyad
glutamate (GLU205 and GLU206) and
tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the
protein-
ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are
drug-like, easy to synthesize, and relatively less toxic than
gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel
antidiabetics.Communicated by Ramaswamy H. Sarma.