期刊
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷 80, 期 -, 页码 197-210出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2018.01.009
关键词
FOXM1; Thiostrepton; Thiazolidinediones; Troglitazone
类别
资金
- Noujaim Fund for Strategic Initiatives, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta
- National Council for Science and Technology (CONACYT)
The FOXM1 protein is a relevant transcription factor involved in cancer cell proliferation. The direct or indirect inhibition of this protein's transcriptional activity by small molecule drugs correlates well with a potentially significant anti-cancer profile, making this macro molecule a promising drug target. There are a few drug molecules reported to interact with (and inhibit) the FOXM1 DNA binding domain (FOXM1-BD), causing downregulation of protein expression and cancer cell proliferation inhibition. Among these drug molecules are the proteasome inhibitor thiostrepton, the former antidiabetic drug troglitazone, and the new FDI-6 molecule. Despite their structural differences, these drugs exert a similar inhibitory profile, and this observation prompted us to study a possible similar mechanism of action. Using a series of molecular dynamics simulations and docking protocols, we identified essential binding interactions exerted by all three classes of drugs, among which, a pi-sulfur interaction (between a His287 and a sulfur containing heterocycle) was the most important. In this report, we describe the preliminary evidence suggesting the presence of a drug-binding pocket within FOXM1 DNA binding domain, in which inhibitors fit to dissociate the protein-DNA complex. This finding suggests a common mechanism of action and a basic framework to design new FOXM1 inhibitors. (C) 2018 Elsevier Inc. All rights reserved.
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