ArticleeLife2023
Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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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.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- An interpretable framework applying protein words to predict protein-small molecule complementary pairing rules.Chemical science · 2026Article
- Computational approaches to druggable site identification: Current status and future perspective.Acta pharmaceutica Sinica. B · 2026Review
- The G Protein Inhibitor YM-254890 is an Allosteric Glue.Journal of molecular biology · 2025Article
- Opening and closing of a cryptic pocket in VP35 toggles it between two different RNA-binding modes.eLife · 2025Article
- Modulation of striated-muscle contractility by a high-affinity myosin-targeting peptide.Biophysical journal · 2025Article
- Discovering cryptic pocket opening and binding of a stimulant derivative in a vestibular site of the 5-HTScience advances · 2025Article
- The G protein inhibitor YM-254890 is an allosteric glue.bioRxiv : the preprint server for biology · 2024Article
- Which cryptic sites are feasible drug targets?Drug discovery today · 2024Review
- Discovery of Trametinib as an orchestrator for cytoskeletal vimentin remodeling.Journal of molecular cell biology · 2024Article
- AlphaFold and Protein Folding: Not Dead Yet! The Frontier Is Conformational Ensembles.Annual review of biomedical data science · 2024Review
- A weak coupling mechanism for the early steps of the recovery stroke of myosin VI: A free energy simulation and string method analysis.PLoS computational biology · 2024Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Homologous mutations in human β, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- PopShift: A Thermodynamically Sound Approach to Estimate Binding Free Energies by Accounting for Ligand-Induced Population Shifts from a Ligand-Free Markov State Model.Journal of chemical theory and computation · 2024Article
- Molecular Dynamics and Other HPC Simulations for Drug Discovery.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Article
- Folding@home: Achievements from over 20 years of citizen science herald the exascale era.Biophysical journal · 2023Review
- Accelerating Cryptic Pocket Discovery Using AlphaFold.Journal of chemical theory and computation · 2023Article
- Local Xenon-Protein Interaction Produces Global Conformational Change and Allosteric Inhibition in Lysozyme.Biochemistry · 2023Article
- From Deep Mutational Mapping of Allosteric Protein Landscapes to Deep Learning of Allostery and Hidden Allosteric Sites: Zooming in on "Allosteric Intersection" of Biochemical and Big Data Approaches.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin's binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R
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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.