Molecular interaction profiling and binding dynamics of Cinnamomum zeylanicum phytochemicals with human pancreatic amylase

Abstract

Diabetes mellitus, characterized by persistent hyperglycemia, remains a critical global health challenge. Inhibition of human pancreatic alpha-amylase, a key enzyme catalyzing carbohydrate digestion, is a promising approach to manage postprandial glucose levels. Cinnamomum zeylanicum, a medicinal plant known for its therapeutic potential, harbors bioactive compounds that can act as natural alpha-amylase inhibitors, though their mechanisms remain underexplored. In this study, molecular docking and 200 ns molecular dynamics (MD) simulations were employed to evaluate the inhibitory potential of 18 phytochemicals derived from Cinnamomum zeylanicum. Two lead compounds, 1HE (1,2,4a,5,6,8a-Hexahydro-1-isopropyl-4,7-dimethylnaphthalene) and C4B (cis-4-Benzyl-2,6-diphenyl-tetrahydropyran), exhibited superior binding affinities (−7.91 and −8.78 kcal/mol, respectively) compared to the FDA-approved inhibitors, acarbose (−8.2 kcal/mol) and miglitol (−5.6 kcal/mol). MD simulations confirmed the stability of the complexes, with RMSD values of 0.21 ± 0.02 nm for 1HE and 0.24 ± 0.03 nm for C4B, showing minimal structural deviations. Structural analyses, including radius of gyration (Rg) and solvent-accessible surface area (SASA), revealed stable and compact protein-ligand conformations. Notably, free energy landscape (FEL) analysis indicated that C4B induces multiple metastable states, suggesting a dynamic inhibitory mechanism potentially involving allosteric regulation. These results highlight 1HE and C4B as promising natural inhibitors with favorable stability, binding characteristics, and inhibitory mechanisms. Further in vitro and in vivo studies are warranted to validate their therapeutic potential as safe and effective alternatives for diabetes management.