Methanol Extract of Coccinia grandis L. Leaves: GC-MS Profiling, Molecular Docking, DFT, and MD Simulations Reveal Phytochemicals as Potential DPP4 Inhibitors

Abstract Diabetes mellitus affects approximately 422 million people worldwide, making dipeptidyl peptidase 4 (DPP4) a promising therapeutic target for glucose-lowering drug development. This study investigated bioactive constituents from Coccinia grandis leaves as potential inhibitors of dipeptidyl peptidase 4 (DPP4), a validated target in type 2 diabetes therapy. GC–MS analysis identified 33 phytochemicals from the methanolic leaf extract. Molecular docking against DPP4 (PDB: 4A5S) revealed cholesteryl chloroformate (–9.3 kcal/mol), β‑sitosterol (–8.6 kcal/mol), and methoxyfenozide (–7.9 kcal/mol) as top ligands forming stable interactions with key catalytic residues. ADME/T predictions indicated acceptable pharmacokinetic behavior and low toxicity. DFT calculations (B3LYP/6‑311G(d,p)) confirmed favorable electronic properties supporting ligand reactivity. Molecular dynamics simulations (100 ns) demonstrated structural stability across complexes, with β‑sitosterol showing the most consistent behavior. The findings suggest that C. grandis phytochemicals represent promising DPP4 inhibitors with potential anti-diabetic properties, necessitating further experimental validation and clinical investigation.