Systematic comparison of competitive and allosteric kinase inhibitors reveals common structural characteristics

• Published in: European journal of medicinal chemistry Vol. 214; p. 113206
• Main Authors: Hu, Huabin, Laufkötter, Oliver, Miljković, Filip, Bajorath, Jürgen
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.03.2021
• Subjects: Adenosine Triphosphate - metabolism; Allosteric inhibitors; Allosteric Regulation - drug effects; ATP-competitive inhibitors; Core structures; Crystallography, X-Ray; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Models, Molecular; Molecular Structure; Phosphotransferases - antagonists & inhibitors; Phosphotransferases - metabolism; Privileged substructures; Protein kinases; Structure-Activity Relationship; X-ray structures; Privileged substructures; Allosteric inhibitors; ATP-competitive inhibitors; Core structures; Protein kinases; X-ray structures
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113206

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. [Display omitted] •Different types of kinase inhibitors were assembled from X-ray structures.•ATP-competitive and allosteric inhibitors were systematically compared.•Close structural relationships between distinct inhibitors were identified.•Small modifications of common cores yielded different types of inhibitors.•Additional targets of crystallographic inhibitors were determined.