期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 48, 期 1, 页码 157-165出版社
AMER CHEMICAL SOC
DOI: 10.1021/ci700313e
关键词
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CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. Structure-based virtual ligand screening computations were performed with FRED, Surflex, and LigandFit, a compound collection of over 310 000 druglike molecules and the crystal structure of CDC25B in order to identify novel classes of ligands. In vitro experiments carried out on a selected list of 1500 molecules led to the discovery of 99 compounds able to inhibit CDC25B activity at 100 mu M. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 mu M). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.
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