Biophysical investigation and conformational analysis of p38α kinase inhibitor doramapimod and its analogues
| Autor: | Amir H. Nasiri, Jan W. Bats, Krishna Saxena, Harald Schwalbe, Hamid R. Nasiri |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology Kinase Stereochemistry Chemistry Microscale thermophoresis Organic Chemistry Pharmaceutical Science Plasma protein binding Dihedral angle Biochemistry Chemical synthesis 03 medical and health sciences Crystallography 030104 developmental biology Drug Discovery Molecular Medicine Kinase binding Pharmacophore Protein kinase A |
| Zdroj: | MedChemComm. 7:1421-1428 |
| ISSN: | 2040-2511 2040-2503 |
| DOI: | 10.1039/c6md00262e |
| Popis: | Doramapimod (BIRB 796) is a potent inhibitor of p38α mitogen-activated protein kinase. It contains an aryl-pyrazole scaffold as a pharmacophore critical for binding. The aryl-pyrazole scaffold is not planar and adopts an out-of-plane conformation, which is described by the torsion angle θ. In this letter, we report the chemical synthesis and biophysical characterization of different analogues of doramapimod (3–12) exhibiting distinctly different aryl-pyrazole torsion angle θ values. The torsion angle θ values of the synthesized analogues (3–6) were determined by crystal structural analysis and the binding affinities to p38α kinase investigated by microscale thermophoresis. Our results unveil a clear correlation between kinase binding and the torsion angle θ of tested doramapimod analogues, highlighting the importance of inhibitor conformation for protein binding. |
| Databáze: | OpenAIRE |
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