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Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
Published on: February 23, 2024
Structural and thermodynamic analyses of interactions between death-associated protein kinase 1 and anthraquinones
Takeshi Yokoyama1, Peter Wijaya1, Yuto Kosaka1
1Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0914, Japan.
Abstract:
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.
Insights
The natural compound purpurin potently inhibits Death-associated protein kinase 1 (DAPK1), a target for various diseases. Its favorable binding thermodynamics suggest purpurin as a promising lead for developing new DAPK1 inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Death-associated protein kinase 1 (DAPK1) is a key regulator of apoptosis and autophagy.
- DAPK1 is implicated as a therapeutic target in conditions such as amyloid-β deposition, endometrial adenocarcinomas, and acute ischemic stroke.
Purpose of the Study:
- To investigate the inhibitory activity of the natural anthraquinone purpurin against DAPK1.
- To elucidate the thermodynamic and structural basis of purpurin's interaction with DAPK1.
Main Methods:
- Enzyme inhibition assays to determine inhibitory activity.
- Thermodynamic analysis (e.g., isothermal titration calorimetry) to characterize binding.
- Crystallographic analysis to visualize the DAPK1-purpurin complex structure.
Main Results:
- Purpurin exhibits potent inhibition of DAPK1 phosphorylation.
- Thermodynamic analysis shows purpurin binding is enthalpically favorable, unlike CPR005231.
- Crystallography reveals a hydrogen-bond network and glycine-rich loop stabilization contributing to binding thermodynamics.
Conclusions:
- Purpurin's potent DAPK1 inhibition and favorable thermodynamics position it as a potential lead compound for drug discovery.
- Understanding the enthalpic contributions to binding can guide the development of novel DAPK1 inhibitors.
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