In Silico Evaluation of Steroidal Alkaloids as Potential Dipeptidyl Peptidase‐4 (DPP‐4) Inhibitors for Type 2 Diabetes Mellitus

ABSTRACT Type 2 diabetes mellitus (T2DM) is a globally known metabolic disorder and a significant health burden that continuously requires improved therapies with enhanced efficacy and safety for effective management. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a recognized class of antidiabetic agents used in treatment of T2DM and is essential to identify novel scaffolds to support the discovery of more potent and safer inhibitors. This study employs integrated in silico approaches to evaluate a curated library of steroidal alkaloids for their potential to act as effective and safe DDP‐4 inhibitors. Compounds were screened for drug likeness, target affinity analyzed by molecular docking, top performing ligands further underwent ADMET screening, and metabolic pathway prediction. Finally, the selected molecules were subjected to molecular dynamics (MD) simulations for 100 ns, MM‐PBSA calculations and density functional theory (DFT) to assess their binding affinity to the target protein. Overall study identified two compounds, SAL1 and SAL2 with favorable binding energy of −11.2 and −10.8 kcal/mol, respectively. Complexes exhibited consistent RMSD, RMSF, and hydrogen bonding patterns during molecular dynamics simulations. Although, experimental validation is required to further confirm this predicted therapeutic potential.