ArticleChemical science2021
Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 49 citations in OpenAlex.
- A marine-derived meroterpenoid inhibits colorectal cancer via PI3K pathway modulation in mice.Marine life science & technology · 2026Article
- Pharmacophore-targeted fluorescence sensing of ibrutinibRSC advances · 2026Article
- UVI5008: the first reversible, non-covalent Bruton's tyrosine kinase epi-inhibitor for B-cell malignancies.Journal of hematology & oncology · 2026Article
- Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.Journal of chemical information and modeling · 2026Article
- Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice.Leukemia · 2025Review
- Covalent and Non-Covalent BTK Inhibition in Chronic Lymphocytic Leukemia Treatment.Current treatment options in oncology · 2025Review
- Probing the Effect of Protein and Inhibitor Conformational Flexibility on the Reaction of Rocelitinib-Like Covalent Inhibitors of Epidermal Growth Factor Receptor. A Quantum Mechanics/Molecular Mechanics Study.Journal of chemical information and modeling · 2025Article
- Size-Dependent Target Engagement of Covalent Probes.Journal of medicinal chemistry · 2025Article
- Covalent Bruton tyrosine kinase inhibitors across generations: A focus on zanubrutinib.Journal of cellular and molecular medicine · 2025Review
- Target fishing: from "needle in haystack" to "precise guidance"--new technology, new strategy and new opportunity.Frontiers in pharmacology · 2025Review
- Multiscale calculations reveal new insights into the reaction mechanism between KRASComputational and structural biotechnology journal · 2024Article
- Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia.Nature reviews. Clinical oncology · 2024Review
- Exploring 2-Sulfonylpyrimidine Warheads as Acrylamide Surrogates for Targeted Covalent Inhibition: A BTK Story.Journal of medicinal chemistry · 2024Article
- Machine learning-based classification models for non-covalent Bruton's tyrosine kinase inhibitors: predictive ability and interpretability.Molecular diversity · 2024Article
- QM/MM Simulations of Afatinib-EGFR Addition: The Role of β-Dimethylaminomethyl Substitution.Journal of chemical theory and computation · 2024Article
- Computational Investigation of the Covalent Inhibition Mechanism of Bruton's Tyrosine Kinase by Ibrutinib.Journal of chemical information and modeling · 2024Article
- Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).Genes · 2023Review
- Structural Complementarity of Bruton's Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Perspective on the Current State-of-the-Art of Quantum Computing for Drug Discovery Applications.Journal of chemical theory and computation · 2022Review
- Exploring the Role of Chemical Reactions in the Selectivity of Tyrosine Kinase Inhibitors.Journal of the American Chemical Society · 2022Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 4 countries.
Funding
Abstract
Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that target BTK. The mechanism of covalent inhibition in BTK has been uncertain because there is no appropriate residue nearby that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. We investigate several mechanisms of covalent modification of C481 in BTK by ibrutinib using combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics reaction simulations. The lowest energy pathway involves direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (Δ
Identifiers
What OpenQuestion holds
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.