ArticleProceedings of the National Academy of Sciences of the United States of America2013
Explaining why Gleevec is a specific and potent inhibitor of Abl kinase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
75 citing papers in PubMed, 155 citations in OpenAlex.
- Absolute Binding Free Energy Calculations between the SARS-CoV-2 Main Protease and 130 Drug Leads Using Implicit Ligand Theory.Journal of chemical information and modeling · 2026Article
- Validation of ion mobility spectrometry - mass spectrometry as a screening tool to identify type II kinase inhibitors of FGFR1 kinase.Rapid communications in mass spectrometry : RCM · 2025Article
- Identification of a Selective Anticancer Agent from a Collection of Complex-And-Diverse Compounds Synthesized from Stevioside.Journal of the American Chemical Society · 2025Article
- CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.The journal of physical chemistry. B · 2024Review
- Molecular basis for differential recognition of an allosteric inhibitor by receptor tyrosine kinases.Proteins · 2024Article
- Computational Investigation of the Covalent Inhibition Mechanism of Bruton's Tyrosine Kinase by Ibrutinib.Journal of chemical information and modeling · 2024Article
- High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids.BJC reports · 2024Article
- Accurate and Efficient Multilevel Free Energy Simulations with Neural Network-Assisted Enhanced Sampling.Journal of chemical theory and computation · 2023Article
- A glimpse of the connection between PPARγ and macrophage.Frontiers in pharmacology · 2023Review
- Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases.eLife · 2022Article
- Novel Tyrosine Kinase Inhibitors to Target Chronic Myeloid Leukemia.Molecules (Basel, Switzerland) · 2022Article
- CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT.Nature communications · 2022Article
- Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.Frontiers in molecular biosciences · 2022Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.The journal of physical chemistry. B · 2021Article
- Protein Loop Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates.The journal of physical chemistry letters · 2021Article
- Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases.The journal of physical chemistry. B · 2021Article
- Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Is Structure-Based Drug Design Ready for Selectivity Optimization?Journal of chemical information and modeling · 2020Article
- Diversity of Long-Lived Intermediates along the Binding Pathway of Imatinib to Abl Kinase Revealed by MD Simulations.Journal of chemical theory and computation · 2020Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Tyrosine kinases present attractive drug targets for specific types of cancers. Gleevec, a well-known therapeutic agent against chronic myelogenous leukemia, is an effective inhibitor of Abl tyrosine kinase. However, Gleevec fails to inhibit closely homologous tyrosine kinases, such as c-Src. Because many structural features of the binding site are conserved, the molecular determinants responsible for binding specificity are not immediately apparent. Some have attributed the difference in binding specificity of Gleevec to subtle variations in ligand-protein interactions (binding affinity control), whereas others have proposed that it is the conformation of the DFG motif, in which ligand binding is only accessible to Abl and not to c-Src (conformational selection control). To address this issue, the absolute binding free energy was computed using all-atom molecular dynamics simulations with explicit solvent. The results of the free energy simulations are in good agreement with experiments, thereby enabling a meaningful decomposition of the binding free energy to elucidate the factors controlling Gleevec's binding specificity. The latter is shown to be controlled by a conformational selection mechanism and also by differences in key van der Waals interactions responsible for the stabilization of Gleevec in the binding pocket of Abl.
Indexed as
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.