ArticleChembiochem : a European journal of chemical biology2013
Using a fragment-based approach to target protein-protein interactions.
Article in Chembiochem : a European journal of chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 126 citations in OpenAlex.
- Toward Comprehensive In Vitro Evaluation of Serum Albumin Binding of Per- and Polyfluoroalkyl Substances.Journal of xenobiotics · 2026Review
- Predicting Affinity Through Homology (PATH): Interpretable binding affinity prediction with persistent homology.PLoS computational biology · 2025Article
- Recent Advances in Omics, Computational Models, and Advanced Screening Methods for Drug Safety and Efficacy.Toxics · 2024Review
- Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson's phenotypes.Nature communications · 2024Article
- Structure-based drug design and molecular dynamics studies of an allosteric modulator targeting the protein-protein interaction site of PDK1.Journal of molecular modeling · 2024Article
- Target-based drug discovery: Applications of fluorescence techniques in high throughput and fragment-based screening.Heliyon · 2024Review
- Common Mechanism of Activated Catalysis in P-loop Fold Nucleoside Triphosphatases-United in Diversity.Biomolecules · 2022Article
- Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization.Life (Basel, Switzerland) · 2022Review
- A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death.Cell chemical biology · 2021Article
- 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
- Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery.Scientific reports · 2021Article
- Nanomolar Protein-Protein Interaction Monitoring with a Label-Free Protein-Probe Technique.Analytical chemistry · 2020Article
- Synthetic Lethality through the Lens of Medicinal Chemistry.Journal of medicinal chemistry · 2020Review
- Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining.Essays in biochemistry · 2020Review
- A novel UCHLCell death & disease · 2019Article
- Biophysical methods in early drug discovery.ADMET & DMPK · 2019Review
- Methods for Discovering and Targeting Druggable Protein-Protein Interfaces and Their Application to Repurposing.Methods in molecular biology (Clifton, N.J.) · 2019Article
- The structure of INI1/hSNF5 RPT1 and its interactions with the c-MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex.The FEBS journal · 2018Article
- Small molecule-based targeting of TTD-A dimerization to control TFIIH transcriptional activity represents a potential strategy for anticancer therapy.The Journal of biological chemistry · 2018Article
- Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).Journal of medicinal chemistry · 2018Article
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Authors and funding
8 authors at 1 institution in 3 countries.
Funding
Abstract
The ability to identify inhibitors of protein-protein interactions represents a major challenge in modern drug discovery and in the development of tools for chemical biology. In recent years, fragment-based approaches have emerged as a new methodology in drug discovery; however, few examples of small molecules that are active against chemotherapeutic targets have been published. Herein, we describe the fragment-based approach of targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51; it makes use of a screening pipeline of biophysical techniques that we expect to be more generally applicable to similar targets. Disruption of this interaction in vivo is hypothesised to give rise to cellular hypersensitivity to radiation and genotoxic drugs. We have used protein engineering to create a monomeric form of RAD51 by humanising a thermostable archaeal orthologue, RadA, and used this protein for fragment screening. The initial fragment hits were thoroughly validated biophysically by isothermal titration calorimetry (ITC) and NMR techniques and observed by X-ray crystallography to bind in a shallow surface pocket that is occupied in the native complex by the side chain of a phenylalanine from the conserved FxxA interaction motif found in BRCA2. This represents the first report of fragments or any small molecule binding at this protein-protein interaction site.
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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.