Natural Anthraquinones as Potential Akt۱-Targeted Anticancer Agents

Background: The phosphoinositide ۳-kinase/protein kinase B (Akt)/mammalian target of the rapamycin signaling pathway is crucial in cancer progression. Akt۱, a vital pathway component, has emerged as a promising therapeutic target. Objectives: This study used molecular docking analysis to investigate the potential of anthraquinones (AQs) as Akt۱ inhibitors. Methods: The crystallographic structure of Akt۱ was obtained from the Protein Data Bank (PDB ID: ۴GV۱). Twenty-one AQ compounds were selected for docking analyses using AutoDock ۴.۰. Binding affinities and interaction modes were compared with two Akt۱ reference inhibitors. Results: Eleven AQs demonstrated substantial binding affinity to the Akt۱’s catalytic site at nanomolar concentrations. Hypericin and sennidin B exhibited the most potent inhibitory effects, with ΔGbinding values of -۱۱.۱۹ kcal/mol and -۱۰.۳۶ kcal /mol, respectively, surpassing control inhibitors. Hypericin formed three hydrogen bonds and two hydrophobic interactions with the Akt۱ catalytic cleft, while sennidin B formed six hydrogen and one hydrophobic interaction. Conclusion: This study identified several AQs, particularly hypericin and sennidin B, as promising Akt۱ inhibitors with superior binding affinities compared to reference compounds. These findings provide a foundation for further developing AQ-based Akt۱-targeted therapeutics in cancer treatment. Future research should focus on the in vitro and in vivo validation of these compounds’ efficacy and safety profiles.