ArticleNature chemical biology2014
A conserved water-mediated hydrogen bond network defines bosutinib's kinase selectivity.
Article in Nature chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 168 citations in OpenAlex.
- Modulating pseudokinase conformation from the ATP-binding site.Structure (London, England : 1993) · 2026Article
- Breaking hydrogen bond network enhances oxygenic photosynthesis of photosystem II.Fundamental research · 2026Article
- Synthetic Substrate Discovery for Hck Kinase via Phage Display.Biochemistry · 2026Article
- Biocatalytic Radical C(spResearch square · 2026Article
- A novel approach for enhancing the potency of kinase inhibitors using topological water networks.Journal of cheminformatics · 2026Article
- Therapeutic Potential ofInternational journal of molecular sciences · 2025Article
- Visualize Transient Water-Mediated Hydrogen Bonds Facilitating the Formation of Enzymatic Near-Attack Conformers.JACS Au · 2025Article
- Water-Based Pharmacophore Modeling in Kinase Inhibitor Design: A Case Study on Fyn and Lyn Protein Kinases.Journal of chemical information and modeling · 2025Article
- SRC is a potential target of Arctigenin in treating triple-negative breast cancer: based on machine learning algorithms, molecular modeling andFrontiers in molecular biosciences · 2025Article
- Novel alloxazine analogues: design, synthesis, and antitumour efficacy enhanced by kinase screening, molecular docking, and ADME studies.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Article
- Classifying protein kinase conformations with machine learning.Protein science : a publication of the Protein Society · 2024Article
- Critical Evaluation of Polarizable and Nonpolarizable Force Fields for Proteins Using Experimentally Derived Nitrile Electric Fields.Journal of the American Chemical Society · 2024Article
- Molecular mechanisms and evolutionary robustness of a color switch in proteorhodopsins.Science advances · 2024Article
- Design, synthesis, and antitumor efficacy of novel 5-deazaflavin derivatives backed by kinase screening, docking, and ADME studies.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Bond-selective fluorescence imaging with single-molecule sensitivity.Nature photonics · 2023Article
- Accounting for Solvation Correlation Effects on the Thermodynamics of Water Networks in Protein Cavities.Journal of chemical information and modeling · 2023Article
- In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders.Journal of chemical information and modeling · 2023Article
- Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1.Journal of medicinal chemistry · 2023Article
- Utilization of Supervised Machine Learning to Understand Kinase Inhibitor Toxophore Profiles.International journal of molecular sciences · 2023Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Kinase inhibitors are important cancer drugs, but they tend to display limited target specificity, and their target profiles are often challenging to rationalize in terms of molecular mechanism. Here we report that the clinical kinase inhibitor bosutinib recognizes its kinase targets by engaging a pair of conserved structured water molecules in the active site and that many other kinase inhibitors share a similar recognition mechanism. Using the nitrile group of bosutinib as an infrared probe, we show that the gatekeeper residue and one other position in the ATP-binding site control access of the drug to the structured water molecules and that the amino acids found at these positions account for the kinome-wide target spectrum of the drug. Our work highlights the importance of structured water molecules for inhibitor recognition, reveals a new role for the kinase gatekeeper and showcases an effective approach for elucidating the molecular origins of selectivity patterns.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.