Departament de Fisicoquímica and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Campus de l'Alimentaió de Torribera, Prat de Riba 171, Edifici Verdaguer, 08921 Santa Coloma de Gramanet, Spain.
Eur J Med Chem. 2013 Feb;60:479-89. doi: 10.1016/j.ejmech.2012.12.014. Epub 2012 Dec 16.
Glycogen synthase kinase 3β (GSK-3β) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimer's disease, mood disorders, diabetes and cancer. Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies. We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor. Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK-3β inhibition by palinurin cannot be competed out by ATP nor peptide substrate. Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3β. Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3β inhibition. The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site. The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action.
糖原合酶激酶 3β（GSK-3β）被广泛认为是多种高发性疾病（如阿尔茨海默病、情绪障碍、糖尿病和癌症）发病机制中的重要参与者。因此，该酶成为开发选择性抑制剂的极具吸引力的治疗靶点，这些抑制剂有望成为治疗这些疾病的新型有前途的药物。本文描述了海洋天然倍半萜化合物 palinurin 作为 GSK-3β抑制剂的分离和生化特性。为了表征抑制机制而进行的实验研究表明，palinurin 对 GSK-3β 的抑制作用不能被 ATP 或肽底物竞争。分子建模技术使我们能够提出与 GSK-3β 的非传统结合模式。此外，分子动力学模拟确定了一种变构机制，通过该机制，palinurin 的结合导致 GSK-3β 的抑制。对一系列结构相关类似物的抑制活性支持 palinurin 的提议结合模式，这是第一个描述靶向该变构位点的化合物。这些结果为设计和开发具有新型作用机制的选择性抑制剂提供了新的机会。
