Abstract:
Mitogen-activated protein kinase kinase 1 (MAPK kinase 1, MEK1) is a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. MEK1 mutations have been reported to lead to abnormal activation that is closely related to the malignant growth and spread of various tumors, making it an important target for cancer treatment. Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Recently, a study showed that modification with dehydroalanine (Dha) can also lead to abnormal activation of MEK1, which has the potential to promote tumor development. In this study, we used molecular dynamics simulations and metadynamics to explore the mechanism of abnormal activation of MEK1 caused by the Dha modification and predicted the inhibitory effects of four FDA-approved MEK1 inhibitors on the Dha-modified MEK1. The results showed that the mechanism of abnormal activation of MEK1 caused by the Dha modification is due to the movement of the active segment, which opens the active pocket and exposes the catalytic site, leading to sustained abnormal activation of MEK1. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors.
摘要:
丝裂原活化蛋白激酶激酶1(MAPK激酶1,MEK1)是丝裂原活化蛋白激酶(MAPK)信号通路中的关键激酶。据报道,MEK1突变导致异常激活,与各种肿瘤的恶性生长和扩散密切相关,使其成为癌症治疗的重要靶点。靶向MEK1,四种小分子药物已被FDA批准,包括曲美替尼,Cobimetinib,Binimetinib,和Selumetinib.最近,一项研究表明,用脱氢丙氨酸(Dha)修饰也可以导致MEK1的异常激活,这可能促进肿瘤的发展。在这项研究中,我们使用分子动力学模拟和元动力学方法探讨了Dha修饰引起MEK1异常激活的机制,并预测了4种FDA批准的MEK1抑制剂对Dha修饰MEK1的抑制作用。结果表明,DHA修饰引起MEK1异常活化的机制是由于活性段的运动,打开活性口袋并暴露催化位点,导致MEK1持续异常激活。在FDA批准的四种抑制剂中,只有Selumetinib通过将活性片段的二级结构从α-螺旋改变为无序环来明确阻断活性位点。我们的研究将有助于解释由Dha修饰引起的MEK1异常激活的机制,并为开发相应的抑制剂提供线索。