Abstract
Background: Eukaryotic elongation factor 2 kinase (eEF2K) regulates the elongation stage of protein synthesis by phosphorylating eEF2, a process related to various diseases including cancer and cardiovascular and neurodegenerative diseases. In this study, we describe the identification of novel eEF2K inhibitors using high-throughput screening fingerprints (HTSFP) generated from predicted profiling of compound-protein interactions (CPIs). Methods: We utilized computationally generated HTSFPs referred to as chemical genomics-based fingerprint (CGBFP). Generally, HTSFPs are generated from multiple biochemical or cell-based assay data. On the other hand, CGBFPs are generated from computational prediction of CPIs using the Chemical Genomics-Based Virtual Screening (CGBVS) method. Therefore, CGBFPs do not have missing information mainly caused by the absence of assay data. Results: Chemogenomics-Based Similarity Profiling (CGBSP) of the screening library (2.6 million compounds) yielded 27 compounds which were evaluated for in vitro eEF2K inhibitory activity. Three compounds with interesting results were identified. Compounds 2 (IC = 11.05 μM) and 4 (IC = 43.54 μM) are thieno[2,3-b]pyridine derivatives that have the same scaffolds with a known eEF2K inhibitor, while compound 13 (IC = 70.13 μM) was a new thiophene-2-amine-type eEF2K inhibitor. Conclusions: CGBSP supplied an efficient strategy in the identification of novel eEF2K inhibitors and provided useful scaffolds for optimization.
Highlights
Protein synthesis is a key process in living cells, being required for creating proteins through translation of mRNAs [1]
The activity of eEF2K is normally dependent on Ca2+ ions and calmodulin (CaM), which binds the N-terminal of its catalytic domain [2,3]. eEF2 is phosphorylated by Eukaryotic elongation factor 2 kinase on Thr56
We proposed the use of the Chemogenomics-Based Similarity Profiling (CGBSP) technique utilizing computationally generated high-throughput screening fingerprints (HTSFP), which we refer to as chemical genomics-based fingerprint (CGBFP)
Summary
Protein synthesis is a key process in living cells, being required for creating proteins through translation of mRNAs [1]. EEF2K was only slightly inhibited by Staurosporine or its derivatives such as K252a or Goe6976 [10]. This feature makes the design of eEF2K inhibitors difficult, since it cannot be based on existing kinase inhibitors. Eukaryotic elongation factor 2 kinase (eEF2K) regulates the elongation stage of protein synthesis by phosphorylating eEF2, a process related to various diseases including cancer and cardiovascular and neurodegenerative diseases. We describe the identification of novel eEF2K inhibitors using high-throughput screening fingerprints (HTSFP) generated from predicted profiling of compound-protein interactions (CPIs). Results: Chemogenomics-Based Similarity Profiling (CGBSP) of the screening library (2.6 million compounds) yielded 27 compounds which were evaluated for in vitro eEF2K inhibitory activity. Conclusions: CGBSP supplied an efficient strategy in the identification of novel eEF2K inhibitors and provided useful scaffolds for optimization
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
