RESUMEN
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.
