In silico Evaluation of Plant-Derived Compounds as Potential α-Amylase Inhibitors for Treatment of Type 2 Diabetes

This study investigates the potential of phytochemical compounds as natural inhibitors of human α-amylase (PDB ID: 1B2Y) for the management of type 2 diabetes mellitus (T2DM). Molecular docking was performed on a library of 3,320 phytochemicals derived from 20 medicinal plants and synthetic anti-diabetic compounds. The top-ranked compounds exhibited superior binding affinities (-11.7 to -18.6 kcal/mol) compared to the control drug Acarbose (-8.7 kcal/mol). Goyaglycoside-g, Goyaglycoside-e, and Momordicoside R emerged as the most potent inhibitors, with Momordicoside R specifically targeting the catalytic residue TYR151. Compounds from Momordica charantia (Kuguacin M, β-Amyrin, α-Amyrin) and Azadirachta indica (Melianoninol, Odoratone) also showed remarkable inhibitory effects. Interaction analysis revealed diverse binding mechanisms, including van der Waals forces, hydrogen bonding, and hydrophobic interactions with key residues such as TYR151 and TRP58. ADME analysis highlighted the challenges of limited bioavailability for some glycosides, while toxicity predictions identified Melianoninol as a promising candidate with a balanced efficacy-safety profile. This study validates the ethnopharmacological use of Momordica charantia and Azadirachta indica in T2DM management and emphasizes the potential of phytochemicals as safer alternatives to synthetic drugs. Future research should focus on structural optimization and advanced formulations to enhance the bioavailability of these compounds. The present analysis demonstrates the superior efficacy of phytochemicals as natural α-amylase inhibitors over synthetic drugs, with identified compounds from Momordica charantia and Azadirachta indica showing 2.14-fold better binding affinity than Acarbose, establishing a foundation for developing safer, bioavailable anti-diabetic therapeutics through computational-guided structural optimization and advanced formulation strategies for clinical translation in type 2 diabetes management.