Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors

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dc.authoridAY, Mehmet/0000-0002-1095-1614
dc.authoridSahin, Kader/0000-0002-9056-9000
dc.authoridComert Onder, Ferah/0000-0002-4037-1979
dc.authoridOzpolat, Bulent/0000-0001-8602-7463
dc.authoridDurdagi, Serdar/0000-0002-0426-0905
dc.contributor.authorOnder, Ferah Comert
dc.contributor.authorDurdagi, Serdar
dc.contributor.authorSahin, Kader
dc.contributor.authorOzpolat, Bulent
dc.contributor.authorAy, Mehmet
dc.date.accessioned2025-01-27T20:29:35Z
dc.date.available2025-01-27T20:29:35Z
dc.date.issued2020
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractEukaryotic elongation factor-2 kinase (eEF-2K) is an unusual alpha kinase commonly upregulated in various human cancers, including breast, pancreatic, lung, and brain tumors. We have demonstrated that eEF-2K is relevant to poor prognosis and shorter patient survival in breast and lung cancers and validated it as a molecular target using genetic methods in related in vivo tumor models. Although several eEF-2K inhibitors have been published, none of them have shown to be potent and specific enough for translation into clinical trials. Therefore, development of highly effective novel inhibitors targeting eEF-2K is needed for clinical applications. However, currently, the crystal structure of eEF-2K is not known, limiting the efforts for designing novel inhibitor compounds. Therefore, using homology modeling of eEF-2K, we designed and synthesized novel coumarin-3-carboxamides including compounds A1, A2, and B1-B4 and evaluated their activity by performing in silico analysis and in vitro biological assays in breast cancer cells. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) area results showed that A1 and A2 have interaction energies with eEF-2K better than those of B1-B4 compounds. Our in vitro results indicated that compounds A1 and A2 were highly effective in inhibiting eEF-2K at 1.0 and 2.5 mu M concentrations compared to compounds B1-B4, supporting the in silico findings. In conclusion, the results of this study suggest that our homology modeling along with in silico analysis may be effectively used to design inhibitors for eEF-2K. Our newly synthesized compounds A1 and A2 may be used as novel eEF-2K inhibitors with potential therapeutic applications.
dc.description.sponsorshipTUBITAK [SBAG215S008]
dc.description.sponsorshipF.C.O. would like to thank TUBITAK for scholarships (SBAG215S008 project and BIDEB 2214A program). This study includes a part of the Ph.D. thesis of F.C.O. The authors thank Canakkale Onsekiz Mart University-COBILTUM Center Laboratory and Cankiri Karatekin University Research Center Laboratory for spectral analysis.
dc.identifier.doi10.1021/acs.jcim.9b01083
dc.identifier.endpage1778
dc.identifier.issn1549-9596
dc.identifier.issn1549-960X
dc.identifier.issue3
dc.identifier.pmid32027127
dc.identifier.scopus2-s2.0-85080031644
dc.identifier.scopusqualityQ1
dc.identifier.startpage1766
dc.identifier.urihttps://doi.org/10.1021/acs.jcim.9b01083
dc.identifier.urihttps://hdl.handle.net/20.500.12428/22987
dc.identifier.volume60
dc.identifier.wosWOS:000526390800063
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherAmer Chemical Soc
dc.relation.ispartofJournal of Chemical Information and Modeling
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WoS_20250125
dc.subjectFactor 2 Kinase
dc.subjectBiological Evaluation
dc.subjectAssay Interference
dc.subjectIn-Vitro
dc.subjectProtein
dc.subjectCancer
dc.subjectRottlerin
dc.subjectApoptosis
dc.subjectBearing
dc.subjectMoiety
dc.titleDesign, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors
dc.typeArticle

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