The biomarkers for diabetes mellitus are numerous. For the treatment of Diabetes Mellitus, there is higher expression of PPAR-gamma, SGLT2, GLP-1, and their upregulated form; consequently, numerous medications were developed that target this protein. The FDA recently approved Vildagliptin's ability to inhibit DPP-IV enzyme (PDB ID-6B1E) in people with diabetes. By computational analysis, we have used Vildagliptin and Twenty Apigenin derivatives against this protein and seven additional proteins that are implicated for DM. For our in silico docking analysis, we used Schrödinger Maestro 2020-3 version, and primary MM-GBSA module was used to determine the relative binding energies of the ligands. Result: Docking study revealed that among all 20 compounds, DPAA3, DPAA5, DPAA6, DPAA7, DPAA12, DPAA13, DPAA16 showed the highest G score than the Vildagliptin against DPP-IV with –10.034, −7.145, − 7.386, − 7.264, 11.212, -8.896 and -9.397 kcal/mol respectively, along with individual G score of Vildagliptin (− 4.86). Prime MM-GBSA analysis gave the relative binding energies of Vildagliptin to 6B1E as –31.07 kcal/mol compared with best-docked compound DPAA12 with −34.86 kcal/mol sequentially. Conclusion: This study sheds light on the Apigenin derivatives that, like Vildagliptin, may function as DPP-IV enzyme inhibitors. Ligand binding energies and ligand strain energies were discovered via additional primary MM-GBSA research.