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Amino Acids. 2017 Jul;49(7):1247-1254. doi: 10.1007/s00726-017-2426-1. Epub 2017 May 4.

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

Author information

1
Department of Urology and Center of Urology, Xiamen Urinary Center, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, People's Republic of China.
2
Department of Urology and Center of Urology, Xiamen Urinary Center, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, People's Republic of China. xiaojuanzzhao@sina.cn.

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:

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

PMID:
28474127
DOI:
10.1007/s00726-017-2426-1
[Indexed for MEDLINE]

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