ArticleMolecular oncology2013
Through the open door: Preferential binding of dasatinib to the active form of BCR-ABL unveiled by in silico experiments.
Article in Molecular oncology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Structure and Dynamics of the ABL1 Tyrosine Kinase and Its Important Role in Chronic Myeloid Leukemia.Archiv der Pharmazie · 2025Review
- Beyond IC50-A computational dynamic model of drug resistance in enzyme inhibition treatment.PLoS computational biology · 2024Article
- Styrylquinazoline derivatives as ABL inhibitors selective for different DFG orientations.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Comparison of molecular responses and outcomes between BCR::ABL1 e14a2 and e13a2 transcripts in chronic myeloid leukemia.Cancer science · 2022Article
- Evaluation of residue variability in a conformation-specific context and during evolutionary sequence reconstruction narrows drug resistance selection in Abl1 tyrosine kinase.Protein science : a publication of the Protein Society · 2022Article
- Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib.Computational and structural biotechnology journal · 2022Article
- Dasatinib-SIK2 Binding Elucidated by Homology Modeling, Molecular Docking, and Dynamics Simulations.ACS omega · 2021Article
- Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex.ACS nano · 2020Article
- Review
- Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites.Nature communications · 2017Article
- Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma.Molecular oncology · 2015Article
- Article
- Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Through the open door: Preferential binding of dasatinib to the active form of BCR-ABL unveiled by in silico experiments.Molecular oncology · 2013Article
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Authors and funding
6 authors.
Funding
Abstract
Dasatinib is a second-generation BCR-ABL inhibitor approved for the treatment of patients with chronic myeloid leukemia, both in the frontline and in the imatinib-resistant/intolerant settings. The high affinity of dasatinib for the protein is currently assumed to result from its ability to bind both the active and inactive conformations of the BCR-ABL kinase. In the present work, using state of the art molecular simulation techniques we prove that dasatinib exhibits a highly selective preference for the active (open) BCR-ABL conformation. By using three different BCR-ABL conformations (active, inactive, and intermediate inactive) we show that, from a thermodynamic standpoint, the affinity of dasatinib for BCR-ABL drastically decreases in the order: active > alternative inactive > inactive, as a result of differential contributions from the single residues lining the kinase binding pocket and the concomitant stabilization/destabilization of the kinase hydrophobic spine. Molecule-pulling experiments also corroborate this trend as significantly lower forces and smaller times are required to extract dasatinib from its inactive BCR-ABL complexes with respect to the active complex counterparts. Importantly, our results support recent NMR solution results demonstrating no evidence of dasatinib bound to the inactive form of BCR-ABL.
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