ArticleACS medicinal chemistry letters2014
Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?
Article in ACS medicinal chemistry letters, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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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.
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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
34 citing papers in PubMed, 55 citations in OpenAlex.
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- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- A Perspective on the Strategic Application of Deconstruction-Reconstruction in Drug Discovery.Journal of medicinal chemistry · 2025Review
- Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel-Lindau E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1α Stabilizers.Journal of medicinal chemistry · 2023Article
- Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods.Journal of chemical information and modeling · 2023Review
- E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology.Journal of medicinal chemistry · 2023Review
- Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.Chemical Society reviews · 2022Review
- Exploring the Surface of the Ectodomain of the PD-L1 Immune Checkpoint with Small-Molecule Fragments.ACS chemical biology · 2022Article
- Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization.Life (Basel, Switzerland) · 2022Review
- Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation.Molecules (Basel, Switzerland) · 2021Review
- Fragment-Based Nuclear Magnetic Resonance Screen against a Regulator of G Protein Signaling Identifies a Binding "Hot Spot".Chembiochem : a European journal of chemical biology · 2021Article
- Applications of Solution NMR in Drug Discovery.Molecules (Basel, Switzerland) · 2021Review
- NMR as a "Gold Standard" Method in Drug Design and Discovery.Molecules (Basel, Switzerland) · 2020Review
- Degradation of proteins by PROTACs and other strategies.Acta pharmaceutica Sinica. B · 2020Review
- Current strategies for the design of PROTAC linkers: a critical review.Exploration of targeted anti-tumor therapy · 2020Review
- Extending the Detection Limit in Fragment Screening of Proteins Using Reverse Micelle Encapsulation.ACS chemical biology · 2019Article
- Spy vs. spy: selecting the best reporter forChemical communications (Cambridge, England) · 2019Article
- Surface Probing by Fragment-Based Screening and Computational Methods Identifies Ligandable Pockets on the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.Journal of medicinal chemistry · 2018Article
- Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA.ChemMedChem · 2018Article
- Approaches to target tractability assessment - a practical perspective.MedChemComm · 2018Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Modulation of protein-protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel-Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α). Careful triaging allowed rescuing weak but specific binding of fragments that would otherwise escape detection at this PPI. Further structural information provided by saturation transfer difference (STD) group epitope mapping, protein-based NMR, competitive isothermal titration calorimetry (ITC), and X-ray crystallography confirmed the binding mode of the rescued fragments. Our findings have important implications for PPI druggability assessment by fragment screening as they reveal an accessible threshold for fragment detection and validation.
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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.