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Structure-based drug design of potential inhibitors of FBXW8, the substrate recognition component of Cullin-RING ligase 7

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Abstract

FBXW8 plays an irreplaceable role in the substrate recognition of ubiquitin-dependent proteolysis, which further regulates cell cycle progression and signal transduction. However, the abnormal expression of FBXW8 triggers malignancy, inflammation, and autophagy irregulation. FBXW8 is considered as an effective therapeutic target for Cullin-RING ligase 7 (CRL7)-related cancers. Still, the lack of selective inhibitors hinders further therapeutic development and limits the exploration of its biological mechanism. This study constructed an integrated protocol that combines pharmacophore modeling, structure-based virtual screening, and Molecular Dynamic Simulation. It was then used as a screening query to identify hit compounds targeted at the substrate recognition site of FBXW8 from a large-scale compound database including 120 million compounds. Then, ten lead compounds were retrieved by using molecular docking analysis and ADMET prediction. Finally, MD simulations were performed to validate the binding stability of selected drug candidates. The result indicated that three newly obtained compounds, namely ZINC96179876, ZINC72174069, and ZINC97730272, might be potent FBXW8 inhibitors against CRL7-related cancers such as endometrial cancer.

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Abbreviations

CRL7:

Cullin-RING ligase 7

FBXW8:

F-box/WD repeat-containing protein 8

CCND1:

Cyclin D1

OCT4:

The octamer binding transcription factor 4

MD:

Molecular dynamics

HPK1:

Mitogen-activated protein kinase 1

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Acknowledgements

This research work was supported by the Doctoral Scientific Fund Project of Henan University of Technology (2019BS050). The Student Academic and Technological Innovation Training Program (GJXY202219) contributed to the research presented in this study. Mr. Sheng Wen and Mr. Yibo Liu are thanked for their technical assistance in preparing figures.

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Authors and Affiliations

  1. Department of Biotechnology, School of Biological Engineering, Henan University of Technology, Zhengzhou, 450001, Henan Province, People’s Republic of China

    Yingying Zhang, Liuqing Cui & Yunpeng Shen

  2. Department of Biotechnology, School of International Education, Henan University of Technology, Zhengzhou, 450001, Henan Province, People’s Republic of China

    Wangji Chen

  3. Institute of Crystallography, Consiglio Nazionale Delle Ricerche (CNR), 70126, Bari, Italy

    Benny Danilo Belviso

  4. State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, People’s Republic of China

    Bin Yu

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by YZ, LC, WC, and YS. The first draft of the manuscript was written by YZ and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yunpeng Shen.

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Zhang, Y., Cui, L., Chen, W. et al. Structure-based drug design of potential inhibitors of FBXW8, the substrate recognition component of Cullin-RING ligase 7. Mol Divers 27, 2257–2271 (2023). https://doi.org/10.1007/s11030-022-10554-x

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