Introduction
Metastases remain a leading cause of cancer-related death, often due to chemotherapy resistance linked to dysregulation of signaling pathways, including PI3K/Akt. AKT1 is a key driver of tumorigenesis, proliferation, and survival, making it an attractive therapeutic target. Natural compounds from plants are being explored as safe and effective agents in cancer therapy.

Methods
A total of 392 phytochemicals from Artemisia annua were screened for AKT1 inhibition. Molecular docking was carried out using InstaDock, and top hits were evaluated through ADMET profiling, PASS analysis, and 500 ns molecular dynamics (MD) simulations. Binding stability was further analyzed with Principal Component Analysis (PCA), Free Energy Landscape (FEL) mapping, and RMSD/RMSF analyses.

Results
Penduletin (docking score −9.4 kcal/mol) and Chrysosplenol D (−9.1 kcal/mol) showed strong binding within the ATP-binding region, forming key interactions with LEU156, GLY157, LYS158, VAL164, and ASP274. MD simulations confirmed complex stability, with average RMSD values of 0.63 nm for AKT1–Penduletin and 0.58 nm for AKT1–Chrysosplenol D, compared to 0.69 nm for apo AKT1. RMSF analysis revealed moderate flexibility of the AKT1 loop region (residues 110–140), which was slightly increased upon ligand binding (0.30 nm for Penduletin and 0.28 nm for Chrysosplenol D), suggesting stable but flexible interactions around the active site. Both compounds met drug-likeness criteria, showed favorable pharmacokinetics, and demonstrated antioxidant, anticarcinogenic, and antineoplastic potential in PASS analysis. FEL analysis indicated energetically stable binding states, supporting their inhibitory activity.

Conclusion
Penduletin and Chrysosplenol D demonstrated strong binding affinity and stable interactions with AKT1. These findings highlight Artemisia annua phytochemicals as promising leads for developing novel cancer therapies.