In Silico Screening of Laminaria japonica Ligands as Potential Inhibitors of DPP-4 for Type 2 Diabetes Treatment

Abstract

Type 2 diabetes mellitus (DM2) is an increasing global health issue marked by insulin resistance and altered glucose homeostasis. Dipeptidyl peptidase-4 (DPP4) is crucial in modulating glucose concentrations through inactivation of incretin hormones. Inhibition of DPP4 constitutes a therapeutic approach for the treatment of DM2. Laminaria japonica, a marine alga, possesses bioactive substances such as fucoidan, beta-ionone, and laminine, which exhibit potential anti-diabetic activities. The chemical interactions of these drugs with DPP4 are still inadequately understood. This work sought to examine the binding interactions of the main Laminaria japonica ligands with DPP4 by molecular docking and molecular dynamics simulations. The study aimed to forecast the binding affinity, stability, and critical interactions of these ligands inside the active site of DPP4. Molecular docking was performed to determine binding energies, succeeded by molecular dynamics simulations lasting 100 ns to assess complex stability. The top three ligands obtained from docking were fucoidan, beta-ionone, and laminin, with binding energies of -5.79 kcal/mol, -5.64 kcal/mol, and -5.6 kcal/mol, respectively, compared to the native ligand PF2, which had a binding energy of -9.21 kcal/mol. However, beta-ionone demonstrated the best ΔTOTAL value of -24.73 kcal/mol in the MD simulation. In conclusion, in silico research indicated that beta-ionone from Laminaria japonica was a potential candidate for DPP4 inhibition and may act as lead compounds for the formulation of innovative anti-diabetic drugs. Additional in vitro and in vivo investigations are necessary to corroborate these results.