Montes Matthieu, Braud Emmanuelle, Miteva Maria A, Goddard Mary-Lorène, Mondésert Odile, Kolb Stéphanie, Brun Marie-Priscille, Ducommun Bernard, Garbay Christiane, Villoutreix Bruno O
UFR biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, Université Paris Descartes, Paris, F-75006, France.
J Chem Inf Model. 2008 Jan;48(1):157-65. doi: 10.1021/ci700313e. Epub 2007 Dec 22.
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 microM. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 microM). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.
细胞周期蛋白磷酸酶25（CDC25）磷酸酶在细胞周期调控中发挥关键作用，是抗癌治疗的有吸引力的靶点。已知几种小分子非肽分子可抑制CDC25，但其中许多似乎与该酶形成共价键或通过催化半胱氨酸硫醇盐基团的氧化起作用。使用FRED、Surflex和LigandFit进行基于结构的虚拟配体筛选计算，一个包含超过310,000个类药物分子的化合物库以及CDC25B的晶体结构，以识别新型配体类别。对1500个分子的选定列表进行的体外实验导致发现了99种能够在100微摩尔浓度下抑制CDC25B活性的化合物。应用了进一步的对接计算，使我们能够提出最有效分子（IC50 = 13微摩尔）的结合模式。我们最好的化合物代表了有前景的新型CDC25抑制剂类别，它们也表现出抗增殖特性。
