Modeling of Cdc25B dual specifity protein phosphatase inhibitors: Docking of ligands and enzymatic inhibition mechanism
Modeling of Cdc25B dual specifity protein phosphatase inhibitors: Docking of ligands and enzymatic inhibition mechanism
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DOI：
10.1002/cmdc.200500092
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发表时间：
2006-05-01
期刊：
影响因子：
3.4
通讯作者：
Novellino, Ettore
中科院分区：
文献类型：
--
作者：
Lavecchia, Antonio;Cosconati, Sandro;Novellino, Ettore
CDC25双特异性磷酸酶在协调细胞信号传递过程和细胞增殖中起着核心作用。据报道，这些酶的不适当扩增或激活是一些人类癌症的显著特征，包括乳腺癌。因此，CDC25磷酸酶的抑制可能为发现新的、选择性的抗肿瘤药物提供一种新的途径。利用Cdc25B的催化域的晶体结构，通过计算对接，建立了各种Cdc25B抑制剂(1-13)与该酶相互作用的结构模型。同时使用两个高效和预测性的对接程序AutoDock和GOLD，允许相互验证预测的绑定姿势。为了评估它们的质量，用已知的结构-活性关系和定点突变数据验证了模型。这些结果为基于结构的配体设计提供了更好的基础，并为所研究的Cdc25B配体的抑制机制提供了可能的解释。我们认为，抑制剂与两个精氨酸残基482和544之间紧密相互作用的重复基序对于可逆酶抑制是最重要的。相反，1-4的不可逆缓蚀机理似乎与苯醌环和Cys473催化硫酸盐的紧密相连有关。我们相信，这一广泛的研究可能为开发新的有效的CDC25B抑制剂作为新型抗癌药物提供有用的线索。
The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs.