Structural Insight into the Interactions between Death-Associated Protein Kinase 1 and Natural Flavonoids

Journal of Medicinal Chemistry
Takeshi YokoyamaMineyuki Mizuguchi

Abstract

Death-associated protein kinase 1 (DAPK1) is a 160 kDa serine/threonine protein kinase that belongs to the Ca(2+)/calmodulin-dependent protein kinase subfamily. DAPK1 is a possible target for the treatment of acute ischemic stroke and endometrial adenocarcinomas. In the present study, we investigated the binding characteristics of 17 natural flavonoids to DAPK1 using a 1-anilinonaphthalene-8-sulfonic acid competitive binding assay and revealed that morin was the strongest binder among the selected compounds. The crystallographic analysis of DAPK1 and 7 selected flavonoid complexes revealed the structure-binding affinity relationship in atomic-level detail. It was suggested that the high affinity of morin could be accounted for by the ionic interaction between 2'-OH and K42 and that such an interaction would not take place with either cyclin-dependent protein kinases or PIM kinases because of their broader entrance regions. Thus, morin would be a more selective inhibitor of DAPK1 than either of these other types of kinases. In addition, we found that the binding of kaempferol to DAPK1 was associated with a chloride ion. The present study provides a better understanding of the molecular properties of the ATP site of DAPK1 and may...Continue Reading

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Citations

Feb 27, 2017·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Sainan LiYuchi Zhang
Jun 28, 2018·Medicinal Research Reviews·Ahmed Karam Farag, Eun Joo Roh
Feb 3, 2018·Scientific Reports·Ahmad Abdullah, Palaniyandi Ravanan
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May 2, 2020·Acta Crystallographica. Section D, Structural Biology·Takeshi YokoyamaMineyuki Mizuguchi
Jun 30, 2019·International Journal of Molecular Sciences·Nami KimTae Ho Lee
Mar 15, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yuan ZhouLing Jiang
Jul 8, 2020·Nutrients·Antonio Pérez-PérezVíctor Sánchez-Margalet
Apr 10, 2020·Current Pharmaceutical Design·Tarique HussainDildar H Kalhoro
Apr 27, 2021·Journal of Chemical Information and Modeling·Sarah Naomi BolzMichael Schroeder
May 15, 2020·Journal of Chemical Information and Modeling·Hao LiangLuhua Lai
Sep 23, 2021·Journal of Medicinal Chemistry·Takeshi YokoyamaMineyuki Mizuguchi

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