In silico inhibition mechanism of α-amylase and α-glucosidase by fragransinic acid and bellericagenin B, two compounds from Combretum fragrans F. Hoffm (Combretaceae)

Diabetes mellitus remains a global health challenge, necessitating novel therapeutic strategies to manage postprandial hyperglycemia. Inhibition of carbohydrate-hydrolyzing enzymes represents a key approach. This study investigates the inhibitory potential of phytochemicals from Combretum fragrans, a Cameroonian medicinal plant traditionally used for diabetes, against these enzymes. Five triterpenoids fragransinic acid (1), betulin (2), betulinic acid (3), bellericagenin B (4), and a mixture of β-sitosterol (5) and stigmasterol (6) were evaluated via molecular docking using HYBRID and FRED protocols. The crystal structures of α-amylase (PDB ID: 1B2Y) and α-glucosidase (PDB ID: 2QMJ) were prepared, and acarbose served as a reference inhibitor. Docking validation confirmed the reliability of the protocols (RMSD < 2 Å). Compounds 1 and 4 exhibited notable binding affinities, with HYBRID scores of -5.6 and -3.7 kcal/mol for α-glucosidase, and -8.1 and -7.3 kcal/mol for α-amylase, respectively. Key interactions included hydrogen bonds with catalytic residues (ASP443, THR205) and extensive Pi-alkyl interactions with aromatic residues (TYR299, TRP539, PHE575). All the compounds demonstrated selective binding modes, suggesting competitive inhibition. This study highlights the potential of C. fragrans triterpenoids as α-amylase and α-glucosidase inhibitors, providing a structural basis for further phytochemical optimization in antidiabetic drug discovery.