ArticleProceedings of the National Academy of Sciences of the United States of America2015
Ligand deconstruction: Why some fragment binding positions are conserved and others are not.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- E-FTMap: A Protein Structure Based Pharmacophore Identification Server for Guiding Fragment Expansion.Journal of molecular biology · 2025Article
- A Perspective on the Strategic Application of Deconstruction-Reconstruction in Drug Discovery.Journal of medicinal chemistry · 2025Review
- Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization.Journal of medicinal chemistry · 2025Article
- Binary mixtures of Vanderbilt University allosteric agonist thermolysis components act as volatile spatial repellents for malaria vector mosquitoes.Pest management science · 2025Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites.Journal of chemical information and modeling · 2024Article
- Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2.Acta crystallographica. Section D, Structural biology · 2023Article
- Exploring the Surface of the Ectodomain of the PD-L1 Immune Checkpoint with Small-Molecule Fragments.ACS chemical biology · 2022Article
- Decomposing compounds enables reconstruction of interaction fingerprints for structure-based drug screening.Journal of cheminformatics · 2022Article
- Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs.Frontiers in pharmacology · 2022Article
- Exploring protein hotspots by optimized fragment pharmacophores.Nature communications · 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
- Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells.FASEB bioAdvances · 2021Article
- Benchmark Sets for Binding Hot Spot Identification in Fragment-Based Ligand Discovery.Journal of chemical information and modeling · 2020Article
- Article
- Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor.Organic & biomolecular chemistry · 2019Article
- qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps.Journal of medicinal chemistry · 2018Article
- Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases.The Journal of biological chemistry · 2018Article
- 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
- Computational Analysis for the Rational Design of Anti-Amyloid Beta (Aβ) Antibodies.The journal of physical chemistry. B · 2018Article
Corrections and comments
- Erratum issuedCorrection for Kozakov et al., Ligand deconstruction: Why some fragment binding positions are conserved and others are not.2015 · Jehle, Sefan [corrected to Jehle, Stefan]
Authors and funding
11 authors.
Funding
Abstract
Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.
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