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Discovery of novel Akt1 inhibitors by an ensemble-based virtual screening method, molecular dynamics simulation, and in vitro biological activity testing

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Abstract

Akt1, as an important member of the Akt family, plays a controlled role in cancer cell growth and survival. Inhibition of Akt1 activity can promote cancer cell apoptosis and inhibit tumor growth. Therefore, in this investigation, a multilayer virtual screening approach, including receptor–ligand interaction-based pharmacophore, 3D-QSAR, molecular docking, and deep learning methods, was utilized to construct a virtual screening platform for Akt1 inhibitors. 17 representative compounds with different scaffolds were identified as potential Akt1 inhibitors from three databases. Among these 17 compounds, the Hit9 exhibited the best inhibitory activity against Akt1 with inhibition rate of 33.08% at concentration of 1 μM. The molecular dynamics simulations revealed that Hit9 and Akt1 could form a compact and stable complex. Moreover, Hit9 interacted with some key residues by hydrophobic, electrostatic, and hydrogen bonding interactions and induced substantial conformation changes in the hinge region of the Akt1 active site. The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were − 34.44, − 63.37, and − 39.14 kJ mol−1, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for develo** new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

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Data availability

The data presented in this study are available on request from the corresponding author.

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Funding

Open access funding provided by the National Natural Science Foundation of China (Grant No. 82260693) and Science and Technology Program Project of Gansu Province (20JR5RA538).

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Authors and Affiliations

  1. College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People’s Republic of China

    Wen Zhang, Mei-Ling Hu, **u-Yun Shi, **ang-Long Chen, Xue Su, Hua-Zhao Qi, Li Yuan & Hui Zhang

  2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Hui Zhang

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  1. Wen Zhang
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Contributions

WZ Investigation, Methodology, Writing-original draft; M-LH Investigation, Validation; X-YS Validation, Formal analysis; X-LC Validation, Data curation; XS and H-ZQ Methodology, Validation; YL Funding acquisition, Project administration; HZ Conceptualization, Writing – review & editing, Project administration, Investigation, Supervision.

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Correspondence to Hui Zhang.

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Zhang, W., Hu, ML., Shi, XY. et al. Discovery of novel Akt1 inhibitors by an ensemble-based virtual screening method, molecular dynamics simulation, and in vitro biological activity testing. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10788-3

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