ArticleScience advances2017
How and when does an anticancer drug leave its binding site?
Article in Science advances, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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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
52 citing papers in PubMed.
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- Microscopic Insights into a Ligand Escape Pathway and Energetics in Leucine-Isoleucine-Valine Binding Protein.ACS omega · 2026Article
- Thermodynamics and Kinetics of the Deintercalation of a Novel Anthracycline from Double-Stranded Oligonucleotide DNA.The journal of physical chemistry. B · 2025Article
- Host-Guest Binding Free Energies à la Carte: An Automated OneOPES Protocol.Journal of chemical theory and computation · 2024Article
- Calculating Protein-Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling.Journal of chemical theory and computation · 2024Article
- Good Rates From Bad Coordinates: The Exponential Average Time-dependent Rate Approach.Journal of chemical theory and computation · 2024Article
- Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.Nature communications · 2024Article
- Mechanism of phosphate release from actin filaments.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Enhanced Sampling with Machine Learning.Annual review of physical chemistry · 2024Review
- Mechanism of Phosphate Release from Actin Filaments.bioRxiv : the preprint server for biology · 2024Article
- Article
- Calculating Protein-Ligand Residence Times Through State Predictive Information Bottleneck based Enhanced Sampling.bioRxiv : the preprint server for biology · 2024Article
- Exploring Kinase Asp-Phe-Gly (DFG) Loop Conformational Stability with AlphaFold2-RAVE.Journal of chemical information and modeling · 2024Article
- Exploring Product Release from Yeast Cytosine Deaminase with Metadynamics.The journal of physical chemistry. B · 2024Article
- Free-Energy Landscape and Rate Estimation of the Aromatic Ring Flips in Basic Pancreatic Trypsin Inhibitors Using Metadynamics.Journal of chemical theory and computation · 2023Article
- Article
- Article
- Predicting Biomolecular Binding Kinetics: A Review.Journal of chemical theory and computation · 2023Review
- Selectivity and Ranking of Tight-Binding JAK-STAT Inhibitors Using Markovian Milestoning with Voronoi Tessellations.Journal of chemical information and modeling · 2023Article
- Quality over quantity: Sampling high probability rare events with the weighted ensemble algorithm.Journal of computational chemistry · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times.
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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.