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Structural and thermodynamic analyses of interactions between death‐associated protein kinase 1 and anthraquinones
Author(s) -
Yokoyama Takeshi,
Wijaya Peter,
Kosaka Yuto,
Mizuguchi Mineyuki
Publication year - 2020
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.374
H-Index - 138
ISSN - 2059-7983
DOI - 10.1107/s2059798320003940
Subject(s) - kinase , serine , chemistry , moiety , protein kinase a , biochemistry , anthraquinones , threonine , stereochemistry , enzyme , biology , microbiology and biotechnology , botany
Death‐associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase that regulates apoptosis and autophagy. DAPK1 is considered to be a therapeutic target for amyloid‐β deposition, endometrial adenocarcinomas and acute ischemic stroke. Here, the potent inhibitory activity of the natural anthraquinone purpurin against DAPK1 phosphorylation is shown. Thermodynamic analysis revealed that while the binding affinity of purpurin is similar to that of CPR005231, which is a DAPK1 inhibitor with an imidazopyridazine moiety, the binding of purpurin was more enthalpically favorable. In addition, the inhibition potencies were correlated with the enthalpic changes but not with the binding affinities. Crystallographic analysis of the DAPK1–purpurin complex revealed that the formation of a hydrogen‐bond network is likely to contribute to the favorable enthalpic changes and that stabilization of the glycine‐rich loop may cause less favorable entropic changes. The present findings indicate that purpurin may be a good lead compound for the discovery of inhibitors of DAPK1, and the observation of enthalpic changes could provide important clues for drug development.