Introduction: The enzyme called dipeptidyl peptidase IV (DPP-IV) is related to the
glycemic control associated with the stimulation of the pancreas to produce insulin. So, its inhibition
is a good strategy for the treatment of type 2 diabetes mellitus.
Methods: In this study, we have employed molecular modeling strategies such as CoMFA, molecular
docking, molecular dynamics, and binding free energy calculations of a set of DPP-IV inhibitors
in order to understand the main characteristics related to the biological activity of these ligands
against the enzyme.
Results: The models obtained from CoMFA presented significant values of internal (0.768) and
external (0.988) validations. Important interactions with some residues, such as Glu205, Tyr666,
Arg125, Ser630, Phe357 and Tyr662, were also identified. In addition, calculations of the electronic
properties allowed relating the LUMO and HOMO energies with the biological activity of the
compounds studied. The results obtained from the molecular dynamics simulations and the SIE
calculations (ΔG) indicated that the inhibitor 40 increases the stability of the DPP-IV target.
Conclusions: Therefore, from this study, it is possible to propose molecular modifications of these
DPP-IV inhibitors in order to improve their potential to treat type 2 diabetes.