de Paula_2024_Chem.Biol.Drug.Des_104_e70016

Type 2 diabetes mellitus is a dramatically increasing global public health challenge. The prevalence is projected almost double, from 194 million in 2003 to 333 million in 2025 with type 2 diabetes mellitus representing approximately 90%-95% of cases. Dual inhibitors for antidiabetic targets is still novel and promising strategy for discovery of more effective therapies. Ester and triazole derivatives of p-coumaric acid were obtained from Williamson synthesis and Microwave-assisted click reaction, respectively. Chemical structures were finely characterized through IR, 1H, and 13C NMR and HRMS. They were tested for their dual inhibitory activity against GSK-3beta kinase and DPP-IV. The complexes resulting from docking were used for all-atom molecular dynamics simulations, including the enzymes in the apo form, using the GROMACS 2022.3. Two inhibitors 2 and 5 demonstrated promising inhibition at low and submicromolar against both proteins. Molecular Dynamic simulations revealed that the binding pattern of the control inhibitors were reproduced by p-coumaric acid derivatives 2 and 5 with crucial interactions involving the same residues. The p-coumaric skeleton can be considered as a promising core for GSK-3beta kinase and DPP-IV dual inhibitors.