ArticleJournal of chemical information and modeling2023
Discovery and Validation of the Binding Poses of Allosteric Fragment Hits to Protein Tyrosine Phosphatase 1b: From Molecular Dynamics Simulations to X-ray Crystallography.
Article in Journal of chemical information and modeling, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Uncovering hidden druggable sites: computational approaches to allosteric and cryptic pocket discovery-from molecular dynamics to AI.Journal of computer-aided molecular design · 2026Review
- From Enhanced Sampling to Human-Readable Representations of Protein Dynamics.Journal of chemical theory and computation · 2026Article
- Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets.Journal of chemical theory and computation · 2026Article
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
- Article
- Molecular dynamics simulation in traditional Chinese medicine research: from molecular mechanisms to multiscale validation.Frontiers in chemistry · 2026Review
- Article
- More Sophisticated Is Not Always Better: A Comparison of Similarity Measures for Unsupervised Learning of Pathways in Biomolecular Simulations.The journal of physical chemistry. B · 2025Article
- The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives.Journal of molecular biology · 2025Review
- Orchestrating function: Concerted dynamics, allostery, and catalysis in protein tyrosine phosphatases.Current opinion in structural biology · 2025Review
- Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies.International journal of molecular sciences · 2025Review
- Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.Journal of chemical information and modeling · 2025Article
- Thermal Titration Molecular Dynamics: The Revenge of the Fragments.Journal of chemical information and modeling · 2025Article
- AlloViz: A tool for the calculation and visualisation of protein allosteric communication networks.Computational and structural biotechnology journal · 2024Article
- Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer.Nature immunology · 2024Article
- An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.Structure (London, England : 1993) · 2024Article
- Exploring Conformational Landscapes Along Anharmonic Low-Frequency Vibrations.The journal of physical chemistry. B · 2024Article
- An expanded view of ligandability in the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.bioRxiv : the preprint server for biology · 2024Article
- High-resolution double vision of the allosteric phosphatase PTP1B.Acta crystallographica. Section F, Structural biology communications · 2024Article
- Biophysical Rationale for the Selective Inhibition of PTP1B over TCPTP by Nonpolar Terpenoids.The journal of physical chemistry. B · 2023Article
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Authors and funding
8 authors.
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Abstract
Fragment-based drug discovery has led to six approved drugs, but the small sizes of the chemical fragments used in such methods typically result in only weak interactions between the fragment and its target molecule, which makes it challenging to experimentally determine the three-dimensional poses fragments assume in the bound state. One computational approach that could help address this difficulty is long-timescale molecular dynamics (MD) simulations, which have been used in retrospective studies to recover experimentally known binding poses of fragments. Here, we present the results of long-timescale MD simulations that we used to prospectively discover binding poses for two series of fragments in allosteric pockets on a difficult and important pharmaceutical target, protein tyrosine phosphatase 1b (PTP1b). Our simulations reversibly sampled the fragment association and dissociation process. One of the binding pockets found in the simulations has not to our knowledge been previously observed with a bound fragment, and the other pocket adopted a very rare conformation. We subsequently obtained high-resolution crystal structures of members of each fragment series bound to PTP1b, and the experimentally observed poses confirmed the simulation results. To the best of our knowledge, our findings provide the first demonstration that MD simulations can be used prospectively to determine fragment binding poses to previously unidentified pockets.
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