DOCKING AND ADMET EVALUATION OF ASTRAGALUS-DERIVED PHYTOCHEMICALS AGAINST GLYCOGEN SYNTHASE KINASE‑3β

Abstract

Glycogen synthase kinase-3β (GSK-3β) regulates cellular processes associated with inflammation, apoptosis, and neurodegeneration and is a validated therapeutic target. Interest in natural compounds capable of interacting with the GSK-3β active site is driven by the toxicity and adverse effects associated with many existing kinase inhibitors. This study aimed to evaluate Astragalus phytocomponents as potential GSK-3β ligands in silico using molecular docking and ADMET prediction. The docking methodology was validated by redocking the native ligand FKB501 from the cocrystallized X-ray structure, yielding an RMSD of 1.83 Å. To assess affinity for the GSK-3β active site, a library of 96 Astragalus compounds was screened. Based on binding affinity and ADMET characteristics, six compounds were selected for detailed analysis: soyasapogenol B, soyasapogenol E, chlorogenic acid, neochlorogenic acid, isoliquiritigenin, and echinatin. Their binding energies were comparable to or exceeded, in absolute value, that of FKB501 (-7.546 kcal/mol), with the lowest values observed for soyasapogenol B (-8.523 kcal/mol) and soyasapogenol E (-8.176 kcal/mol). Interaction analysis revealed key active-site residues, including Ile62, Phe67, Val70, Ala83, Lys85, Val135, Gln185, Leu188, Cys199, and Asp200. ADMET prediction indicated that isoliquiritigenin and echinatin had the most balanced pharmacological and toxicological profiles, whereas sapogenins, despite their higher docking affinity, were limited by low solubility and high lipophilicity. The selected Astragalus phytocomponents are therefore promising candidates for further experimental evaluation as potential GSK-3β inhibitors.