In silico evaluation of herbal inhibitors against AKT isoforms as potential anticancer agents

Protein kinase B (AKT) isoforms are important kinases regulating fundamental biological processes such as cellular growth, metabolism, and apoptosis. Targeting these isoforms is critical for the development of therapeutic strategies in cancer. In this study, we evaluated 107 phytochemicals against AKT1, AKT2, and AKT3 using molecular docking, protein flexibility simulations, and ADMET profiling. Molecular docking revealed that isoangustone A (-9.8 kcal/mol) and lupalbigenin (-9.7 kcal/mol) exhibited stronger binding to AKT1 than the reference drug capivasertib (-9.2 kcal/mol). Cudraflavone B (-10.8 kcal/mol) and lupalbigenin (-10.4 kcal/mol) out performed capivasertib (-9.1 kcal/mol) against AKT2, while marein (-9.5 kcal/mol) and pristimerin (-9.4 kcal/mol) surpassed capivasertib (-8.9 kcal/mol) for AKT3. Protein flexibility analysis indicated stable ligand–protein complexes, and ADMET evaluation showed acceptable drug-likeness with some limitations, such as low Caco-2 permeability for certain compounds. These findings highlight promising lead compounds for AKT isoform inhibition; however, isoangustone A exhibits predicted hERG II inhibition, raising significant cardiotoxicity concerns that represent a major development barrier. The results are predictive and require in vitro cardiac safety profiling alongside in vivo validation before clinical advancement.