Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L3N6, Canada.
Molecules. 2023 Jan 21;28(3):1095. doi: 10.3390/molecules28031095.
The α-kinase, eEF2K, phosphorylates the threonine 56 residue of eEF2 to inhibit global peptide elongation (protein translation). As a master regulator of protein synthesis, in combination with its unique atypical kinase active site, investigations into the targeting of eEF2K represents a case of intense structure-based drug design that includes the use of modern computational techniques. The role of eEF2K is incredibly diverse and has been scrutinized in several different diseases including cancer and neurological disorders-with numerous studies inhibiting eEF2K as a potential treatment option, as described in this paper. Using available crystal structures of related α-kinases, particularly MHCKA, we report how homology modeling has been used to improve inhibitor design and efficacy. This review presents an overview of eEF2K related drug discovery efforts predating from the 1990's, to more recent in vivo studies in rat models. We also provide the reader with a basic introduction to several approaches and software programs used to undertake such drug discovery campaigns. With the recent exciting publication of an eEF2K crystal structure, we present our view regarding the future of eEF2K drug discovery.
α-激酶 eEF2K 通过磷酸化 eEF2 的苏氨酸 56 残基来抑制全球肽延伸（蛋白质翻译）。作为蛋白质合成的主要调节剂，结合其独特的非典型激酶活性位点，对 eEF2K 的靶向研究代表了一种基于结构的药物设计的案例，包括使用现代计算技术。eEF2K 的作用非常多样化，在包括癌症和神经紊乱在内的几种不同疾病中进行了研究——许多研究将抑制 eEF2K 作为一种潜在的治疗选择，本文对此进行了描述。利用相关α-激酶（特别是 MHCKA）的现有晶体结构，我们报告了同源建模如何用于改进抑制剂的设计和功效。本综述概述了从 20 世纪 90 年代开始的与 eEF2K 相关的药物发现工作，以及最近在大鼠模型中的体内研究。我们还为读者提供了一些用于开展此类药物发现活动的方法和软件程序的基本介绍。随着 eEF2K 晶体结构的最新发布，我们提出了对 eEF2K 药物发现未来的看法。
