Systematic comparison of competitive and allosteric kinase inhibitors reveals common structural characteristics
| Autor: | Filip Miljković, Huabin Hu, Oliver Laufkötter, Jürgen Bajorath |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Kinase Chemistry Phosphotransferases Organic Chemistry Allosteric regulation General Medicine Computational biology Crystallography X-Ray 01 natural sciences 0104 chemical sciences Structure-Activity Relationship 03 medical and health sciences Adenosine Triphosphate Allosteric Regulation Drug Discovery Humans Enzyme Inhibitors 030304 developmental biology |
| Zdroj: | European Journal of Medicinal Chemistry. 214:113206 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2021.113206 |
| Popis: | Allosteric and ATP-competitive kinase inhibitors act by distinct mechanisms and are expected to have high and low kinase selectivity, respectively. This also raises the question whether or not these different types of inhibitors might be structurally distinct. To address this question, we have assembled data sets of currently available competitive and allosteric kinase inhibitors confirmed by X-ray crystallography and systematically compared these compounds on the basis of different structural criteria. Many competitive and allosteric inhibitors were found to contain the same or similar substructures and a subset of allosteric inhibitors was found to share core structures with ATP site-directed inhibitors. In some instances, small chemical modifications of common cores were found to yield either allosteric or competitive inhibitors. Hence, these different categories of inhibitors with distinct mechanisms of action were often structurally related and represented much more of a structural continuum than discrete states. Additional target annotations were frequently identified for competitive inhibitors, but were rare for allosteric inhibitors. As a part of this study, our collection of kinase inhibitors and the associated information are made freely available to enable further assessment of chemical modifications that distinguish similar kinase inhibitors with distinct mechanisms of action. |
| Databáze: | OpenAIRE |
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