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C-Jun N-terminal kinase inhibitors: Structural insight into kinase-inhibitor complexes.
Computational and Structural Biotechnology Journal ( IF 6 ) Pub Date : 2020-06-12 , DOI: 10.1016/j.csbj.2020.06.013
Men Thi Hoai Duong 1 , Joon-Hwa Lee 2 , Hee-Chul Ahn 1
Affiliation  

The activation of c-Jun N-terminal kinases (JNKs) plays an important role in physiological processes including neuronal function, immune activity, and development, and thus, JNKs have been a therapeutic target for various diseases such as neurodegenerative diseases, inflammation, and cancer. Efforts to develop JNK-specific inhibitors have been ongoing for several decades. In this process, the structures of JNK in complex with various inhibitors have contributed greatly to the design of novel compounds and to the elucidation of structure-activity relationships. Almost 100 JNK structures with various compounds have been determined. Here we summarize the information gained from these structures and classify the inhibitors into several groups based on the binding mode. These groups include inhibitors in the open conformation and closed conformation of the gatekeeper residue, non-ATP site binders, peptides, covalent inhibitors, and type II kinase inhibitors. Through this work, deep insight into the interaction of inhibitors with JNKs can be gained and this will be helpful for developing novel, potent, and selective inhibitors.



中文翻译:

C-Jun N末端激酶抑制剂:激酶抑制剂复合物的结构见解。

c-Jun N末端激酶(JNKs)的激活在包括神经元功能,免疫活性和发育在内的生理过程中起着重要作用,因此,JNKs已成为多种疾病的治疗靶标,例如神经退行性疾病,炎症和癌症。开发JNK特异性抑制剂的努力已经进行了数十年。在此过程中,与各种抑制剂复合的JNK的结构为新型化合物的设计和结构-活性关系的阐明做出了巨大贡献。已经确定了具有各种化合物的近100种JNK结构。在这里,我们总结了从这些结构中获得的信息,并根据结合模式将抑制剂分为几类。这些组包括关守残基的开放构象和封闭构象的抑制剂,非ATP位点结合剂,肽,共价抑制剂和II型激酶抑制剂。通过这项工作,可以深入了解抑制剂与JNK的相互作用,这将有助于开发新型,有效和选择性的抑制剂。

更新日期:2020-06-12
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