ArticleAngewandte Chemie (International ed. in English)2022
Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases.
Article in Angewandte Chemie (International ed. in English), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 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
21 citing papers in PubMed.
- ModBindProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Altered residence time as a cause of drug resistance.Current opinion in structural biology · 2026Review
- Enhanced Sampling in the Age of Machine Learning: Algorithms and Applications.Chemical reviews · 2026Review
- Machine Learning-Augmented Molecular Dynamics Simulations (MD) Reveal Insights Into the Disconnect Between Affinity and Activation of ZTP Riboswitch Ligands.Angewandte Chemie (International ed. in English) · 2025Article
- Detection of Putative Ligand Dissociation Pathways in Proteins Using Site-Identification by Ligand Competitive Saturation.Journal of chemical information and modeling · 2025Article
- Pathway Specific Unbinding Free Energy Profiles of Ritonavir Dissociation from HIV-1 Protease.Biochemistry · 2025Article
- Calculating Protein-Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling.Journal of chemical theory and computation · 2024Article
- Enhanced Sampling with Machine Learning.Annual review of physical chemistry · 2024Review
- 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
- Data-driven classification of ligand unbinding pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Allo-targeting of the kinase domain: Insights from in silico studies and comparison with experiments.Current opinion in structural biology · 2024Review
- Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters.Mini reviews in medicinal chemistry · 2024Review
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- Article
- Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses.JACS Au · 2023Article
- Good Things Take Time: Tiwary-Seeliger Collaboration for Predictive Pharmacodynamics.Angewandte Chemie (International ed. in English) · 2023Article
- Selectivity and Ranking of Tight-Binding JAK-STAT Inhibitors Using Markovian Milestoning with Voronoi Tessellations.Journal of chemical information and modeling · 2023Article
- Probing conformational landscapes and mechanisms of allosteric communication in the functional states of the ABL kinase domain using multiscale simulations and network-based mutational profiling of allosteric residue potentials.The Journal of chemical physics · 2022Article
- Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.Frontiers in molecular biosciences · 2022Article
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.
Funding
Abstract
Understanding how mutations render a drug ineffective is a problem of immense relevance. Often the mechanism through which mutations cause drug resistance can be explained purely through thermodynamics. However, the more perplexing situation is when two proteins have the same drug binding affinities but different residence times. In this work, we demonstrate how all-atom molecular dynamics simulations using recent developments grounded in statistical mechanics can provide a detailed mechanistic rationale for such variances. We discover dissociation mechanisms for the anti-cancer drug Imatinib (Gleevec) against wild-type and the N368S mutant of Abl kinase. We show how this point mutation triggers far-reaching changes in the protein's flexibility and leads to a different, much faster, drug dissociation pathway. We believe that this work marks an efficient and scalable approach to obtain mechanistic insight into resistance mutations in biomolecular receptors that are hard to explain using a structural perspective.
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.