Computational assessment of substituted 2-Mercaptobenzimidazole Schiff bases derivatives targeting α-amylase, α-glucosidase, and PPAR-γ receptor in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder marked by elevated blood glucose levels due to insulin resistance and impaired insulin secretion. Current therapeutic strategies often focus on inhibiting carbohydrate-hydrolyzing enzymes such as α-Amylase (PDB ID: 4GQR; Human Pancreatic α-amylase in complex with myricetin) and α-Glucosidase (PDB ID: 3TOP; C-terminal subunit of Human Maltase-Glucoamylase in complex with acarbose) to reduce postprandial hyperglycemia. Additionally, increasing insulin sensitivity is mostly dependent on PPAR-γ receptor (PDB ID: 1QSE; Peroxisome Proliferator-Activated Receptor Gamma, crystal structure of human A6-TCR bound to HLA-A2 complexed with altered HTLV-1 Tax peptide V7R) activity. In this study, a computational docking approach was employed to assess the antidiabetic potential of fifteen substituted 2-mercaptobenzimidazole Schiff base derivatives targeting α-amylase, α-glucosidase, and PPAR-γ receptor. Molecular docking was conducted using AutoDock Tools version 1.5.7 to evaluate binding affinity and interaction profiles. As the standard reference medication, acarbose was employed. Among the designed compounds, five derivatives showing the highest binding affinity were selected for detailed comparative analysis. The docking results revealed that several compounds demonstrated competitive binding energies and stable interactions within the active sites of the target proteins relative to acarbose. Key interactions included hydrogen bonds and hydrophobic contacts with catalytically important amino acids. These findings suggest that substituted 2-mercaptobenzimidazole Schiff bases possess competitive inhibitory potential and may serve as promising lead candidates for multi-target antidiabetic therapy. The study provides valuable insight for further in vitro validation and potential lead optimization in the development of novel antidiabetic therapies.