期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 24, 页码 9680-9696出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01616
关键词
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资金
- Region Languedoc-Roussillon (Program Chercheurs d'Avenir)
- Institut National du Cancer (INCa) [2010-200]
- Agence Nationale de la Recherche (ANR Programme Blanc) [2011-SIMI7]
We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hernatological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against that act in a synergistic mariner with well-known antitumoral agents.
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