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Amino Acids

, Volume 49, Issue 7, pp 1247–1254 | Cite as

Conformational stabilization of FOX–DNA complex architecture to sensitize prostate cancer chemotherapy

  • Bin Chen
  • Huiqiang Wang
  • Zhun Wu
  • Bo Duan
  • Peide Bai
  • Kaiyan Zhang
  • Wei Li
  • Jiaxin Zheng
  • Jinchun XingEmail author
Original Article

Abstract

The forkhead box (FOX) transcription factor is a family of tumor suppressors that negatively regulates the tumorigenesis activity of prostate cancer; stabilization of FOX–DNA complex architecture has been recognized as a new and promising strategy for sensitizing cancer chemotherapy. Here, we described a systematic method that combined in silico analysis and in vitro assay to investigate the intermolecular interaction between FOX DNA-binding domain (DBD) and its cognate DNA partner. The structural and energetic information harvested from the molecular investigation were used to guide high-throughput virtual screening against a structurally diverse, nonredundant library of natural product compounds, aiming at discovery of novel small-molecule medicines that can conformationally stabilize and promote FOX–DNA recognition and interaction. The screening identified a number of theoretically promising hits, which were then examined by using fluorescence anisotropy assay to determine their binding potency for FOX DBD domain. The antitumor activity of identified high-affinity compounds was also tested at cellular level. Structural dynamics analysis found that the small-molecule stabilizers can shift the conformational equilibrium of FOX DBD to DNA-bound state, thus promoting the protein domain to bind tightly with its DNA partner.

Keywords

Forkhead box High-throughput virtual screening Structural dynamics Chemotherapy Prostate cancer 

Notes

Acknowledgements

This work was supported by The First Affiliated Hospital of Xiamen University.

Compliance with ethical standards

Conflict of interest

The authors confirm that this article content has no conflict of interests.

Statement of informed consent

Not applicable.

Statement of human and animal rights

Not applicable.

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Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  • Bin Chen
    • 1
  • Huiqiang Wang
    • 1
  • Zhun Wu
    • 1
  • Bo Duan
    • 1
  • Peide Bai
    • 1
  • Kaiyan Zhang
    • 1
  • Wei Li
    • 1
  • Jiaxin Zheng
    • 1
  • Jinchun Xing
    • 1
    Email author
  1. 1.Department of Urology and Center of Urology, Xiamen Urinary CenterThe First Affiliated Hospital of Xiamen UniversityXiamenPeople’s Republic of China

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