ArticleJournal of medicinal chemistry2015
Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers.
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Who cites it
125 citing papers in PubMed, 233 citations in OpenAlex.
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- A curated benchmark for cofolding models on kinase conformational states.npj drug discovery · 2026Article
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- Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer.RSC advances · 2026Review
- p21-Activated Kinase (PAK) Group I-Targeting Inhibitors Promote the Dimeric Conformation in Live Cells.ACS chemical biology · 2026Article
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- Mechanism of and research progress on alterations in the RET gene in thyroid cancer (Review).Molecular medicine reports · 2026Review
- Polypharmacology is an enduring and nearly universal property of kinase inhibitors.bioRxiv : the preprint server for biology · 2026Article
- Results of a Large-Scale Study of the Binding of 50 Type II Inhibitors to 348 Kinases: The Role of Protein Reorganization.Journal of medicinal chemistry · 2026Article
- KinConfBench: A Curated Benchmark for Cofolding Models on Kinase Conformational States.bioRxiv : the preprint server for biology · 2026Article
- Ligand-based graph neural network, molecular dynamics and biological evaluation for identification of potential FGFR1 kinase inhibitors.Molecular diversity · 2026Article
- Results of a large scale study of the binding of 50 type II inhibitors to 348 kinases: The role of protein reorganization.bioRxiv : the preprint server for biology · 2026Article
65 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Structural coverage of the human kinome has been steadily increasing over time. The structures provide valuable insights into the molecular basis of kinase function and also provide a foundation for understanding the mechanisms of kinase inhibitors. There are a large number of kinase structures in the PDB for which the Asp and Phe of the DFG motif on the activation loop swap positions, resulting in the formation of a new allosteric pocket. We refer to these structures as "classical DFG-out" conformations in order to distinguish them from conformations that have also been referred to as DFG-out in the literature but that do not have a fully formed allosteric pocket. We have completed a structural analysis of almost 200 small molecule inhibitors bound to classical DFG-out conformations; we find that they are recognized by both type I and type II inhibitors. In contrast, we find that nonclassical DFG-out conformations strongly select against type II inhibitors because these structures have not formed a large enough allosteric pocket to accommodate this type of binding mode. In the course of this study we discovered that the number of structurally validated type II inhibitors that can be found in the PDB and that are also represented in publicly available biochemical profiling studies of kinase inhibitors is very small. We have obtained new profiling results for several additional structurally validated type II inhibitors identified through our conformational analysis. Although the available profiling data for type II inhibitors is still much smaller than for type I inhibitors, a comparison of the two data sets supports the conclusion that type II inhibitors are more selective than type I. We comment on the possible contribution of the DFG-in to DFG-out conformational reorganization to the selectivity.
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