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Cited by 11Computational Drug Discovery MethodsProtein Structure and DynamicsProtein Kinase Regulation and GTPase Signaling

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eEF2K Inhibitor Design: The Progression of Exemplary Structure-Based Drug Design

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Klupt, Kody A., Jia, Zongchao·2023·Molecules
DOI 10.3390/molecules28031095PMC PMC9921739
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Abstract

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.

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  • All available eEF2K compounds remain experimental, with unresolved issues in kinase selectivity, brain exposure, and chronic tolerability.

    “Despite consistent neuroprotective- and plasticity-enhancing effects across preclinical disease models, all available compounds remain experimental, with unresolved issues in kinase selectivity, brain exposure, and chronic tolerability [159,160,161].”

    From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [161]

    Section 4.2 states that, to the authors’ knowledge, there had been no human clinical trials of eEF2K inhibitors, supporting the description of the compounds as experimental. The Concluding Remarks (section 8) likewise say that their effects in human trials remain to be demonstrated. The paper does not establish the claimed unresolved issues in kinase selectivity, brain exposure, or chronic tolerability; section 6.3 discusses specificity and toxicity only as general goals of lead-compound optimization. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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Metadata

Authors
Klupt, K. A., & Jia, Z.
Affiliations
Queen's University (CA)
Corresponding author
Jia, Zongchao
ORCID
Jia, Zongchao
Venue
Molecules
Publisher
MDPI AG
Published
2023-01-21
Volume
28
Issue
3
Pages
1095
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules28031095
PMC
PMC9921739
OpenAlex
W4317721588
Cited by
11
References
4
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 1
FWCI
0.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-04427)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
eEF2K, structure-based drug design, eEF2 phosphorylation, translational regulation, homology modeling, crystal structure, kinase inhibitors, cancer therapy, neurological disorders, history of drug discovery
MeSH terms
Animals, Neoplasms, Phosphorylation, Protein Processing, Post-Translational, Drug Design, Signal Transduction, Rats, Elongation Factor 2 Kinase

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