Multi‐Level Computational Screening of Artemisia annua Phytochemicals Identifies Penduletin and Chrysosplenol D as Promising AKT1 Inhibitors Through Docking, ADMET, PASS, Molecular Dynamics, PCA, and FEL Analyses

ABSTRACT Metastasis remains a major cause of cancer mortality, often linked to chemotherapy resistance driven by dysregulated pathways such as PI3K/Akt. AKT1 plays a central role in tumorigenesis, proliferation, and survival, making it an attractive therapeutic target. Here, 392 phytochemicals from Artemisia annua were screened against AKT1 using InstaDock, followed by ADMET, PASS, and molecular dynamics analyses to identify potential natural inhibitors. Virtual screening led to the identification of Penduletin (−8.5 kcal/mol) and Chrysosplenol D (−8.9 kcal/mol) as potential candidates in comparison of Capivasertib (‐7.8 kcal/mol), both candidates showed superior binding inside the ATP‐binding region by LEU156, GLY157, LYS158, and VAL164 and the proton acceptor site with ASP274 residue. These compounds satisfied drug‐likeness criteria, showed favorable pharmacokinetic profiles, and exhibited predicted antioxidant, anticarcinogenic, and antineoplastic activities in PASS analysis. MD simulations (500 ns) confirmed stable AKT1 complexes, supported by RMSD, RMSF, R g , SASA, and hydrogen‐bond analyses, comparable to Capivasertib. PCA and FEL analyses further indicated reduced conformational flexibility and energetically favorable AKT1 states. In combination, these results demonstrate that Penduletin and Chrysosplenol D can be potential selective AKT1 inhibitors from Artemisia annua which can serve as potent natural therapeutic leads for cancer therapy.