In silico and Network Pharmacology Identification of Acacia senegal Phytochemicals as Potential α-Amylase Inhibitors.

INTRODUCTION Diabetes mellitus is a rapidly expanding chronic disease, prompting interest in plant-derived natural products as adjuncts to conventional therapy because of their improvements in glycaemic control and reduced complications. To evaluate phytochemicals' potential as α-amylase inhibitors using an integrated in-silico workflow.

Methods

Acacia senegal phytochemicals retrieved from the IMPPAT 2.0 database were evaluated their in-silico studies against α-amylase inhibitors using molecular docking, DFT, pharmacokinetic and toxicity profiling, in addition to PASS prediction, network pharmacology and MD simulations.

Results

Docking of 31 compounds was carried out, and the top three ligands, which are: IMPHY014840 (-9.321 kcal/mol), IMPHY014838 (-9.208 kcal/mol) and IMPHY006972 (-9.026 kcal/mol), were selected. Their favorable binding energies indicated strong predicted affinity toward the selected enzyme target. DFT calculations showed identical HOMO-LUMO gaps of 6.936 eV for the first two ligands, whereas the third one displayed a larger gap of 9.484 eV, indicating lower chemical reactivity. Furthermore, pharmacokinetic screening indicated high human intestinal absorption (75-86 %) and favorable Caco-2 permeability for the top three compounds, particularly for IMPHY014840 and IMPHY014838. PASS analysis suggested protease target affinity for IMPHY014840 and GPCR/transcription factor activity for IMPHY014838, expanding their therapeutic scope beyond α-amylase inhibition. MD trajectories confirmed overall complex stability, with IMPHY014838 exhibiting marginally lower ligand RMSD and therefore slightly superior dynamical stability.

Discussion

The present study identified IMPHY014840 and IMPHY014838 as promising α- amylase inhibitors, with docking scores of -9.321 and -9.208 kcal/mol, respectively. DFT, ADMET, toxicity, PASS, and 100 ns MD simulations indicate stable enzyme-ligand binding, high predicted intestinal absorption, and multitarget potential. Network pharmacology further suggests that these compounds act on a broad set of diabetes related targets, supporting their value as antidiabetic lead candidates.

Conclusion

The combined computational evidence supports IMPHY014840 and IMPHY014838 as promising natural α-amylase inhibitors for type 2 DM management, and recommends in vitro, in vivo, and formulation optimization to address their limitations.