ArticleThe journal of physical chemistry. B2021
Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.
Article in The journal of physical chemistry. B, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 29 citations in OpenAlex.
- Advances and Challenges in Milestoning Simulations for Drug-Target Kinetics.Journal of chemical theory and computation · 2024Article
- Quantitative Prediction of Dissociation Rates of PYK2 Ligands Using Umbrella Sampling and Milestoning.Journal of chemical theory and computation · 2024Article
- Allo-targeting of the kinase domain: Insights from in silico studies and comparison with experiments.Current opinion in structural biology · 2024Review
- Predicting Biomolecular Binding Kinetics: A Review.Journal of chemical theory and computation · 2023Review
- Article
- Perspective: Path Sampling Methods Applied to Enzymatic Catalysis.Journal of chemical theory and computation · 2022Review
- Simulation of ligand dissociation kinetics from the protein kinase PYK2.Journal of computational chemistry · 2022Article
- Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases.Angewandte Chemie (International ed. in English) · 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
- Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.Frontiers in molecular biosciences · 2022Article
- Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- 15 Years of molecular simulation of drug-binding kinetics.Expert opinion on drug discoveryReview
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Gleevec (a.k.a., imatinib) is an important anticancer (e.g., chronic myeloid leukemia) chemotherapeutic drug due to its inhibitory interaction with the Abl kinase. Here, we use atomically detailed simulations within the Milestoning framework to study the molecular dissociation mechanism of Gleevec from Abl kinase. We compute the dissociation free energy profile, the mean first passage time for unbinding, and explore the transition state ensemble of conformations. The milestones form a multidimensional network with average connectivity of about 2.93, which is significantly higher than the connectivity for a one-dimensional reaction coordinate. The free energy barrier for Gleevec dissociation is estimated to be ∼10 kcal/mol, and the exit time is ∼55 ms. We examined the transition state conformations using both, the committor and transition function. We show that near the transition state the highly conserved salt bridge K217 and E286 is transiently broken. Together with the calculated free energy profile, these calculations can advance the understanding of the molecular interaction mechanisms between Gleevec and Abl kinase and play a role in future drug design and optimization studies.
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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.