Arantes Guilherme Menegon
Departamento de Bioquimica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
J Phys Chem B. 2008 Nov 27;112(47):15244-7. doi: 10.1021/jp8070019.
The development of anticancer therapeutics that target Cdc25 phosphatases is now an active area of research. A complete understanding of the Cdc25 catalytic mechanism would certainly allow a more rational inhibitor design. However, the identity of the catalytic acid used by Cdc25 has been debated and not established unambiguously. Results of molecular dynamics simulations with a calibrated hybrid potential for the first reaction step catalyzed by Cdc25B in complex with its natural substrate, the Cdk2-pTpY/CycA protein complex, are presented here. The calculated reaction free-energy profiles are in very good agreement with experimental measurements and are used to discern between different proposals for the general acid. In addition, the simulations give useful insight on interactions that can be explored for the design of inhibitors specific to Cdc25.
靶向Cdc25磷酸酶的抗癌治疗药物的研发目前是一个活跃的研究领域。全面了解Cdc25催化机制肯定有助于更合理地设计抑制剂。然而，Cdc25所使用的催化酸的身份一直存在争议，尚未明确确定。本文展示了利用校准的混合势对Cdc25B与其天然底物Cdk2-pTpY/CycA蛋白复合物催化的第一步反应进行分子动力学模拟的结果。计算得到的反应自由能分布与实验测量结果非常吻合，并用于区分关于通用酸的不同提议。此外，模拟为设计针对Cdc25的特异性抑制剂可探索的相互作用提供了有用的见解。
