ArticleActa crystallographica. Section D, Structural biology2021
Frag4Lead: growing crystallographic fragment hits by catalog using fragment-guided template docking.
Article in Acta crystallographica. Section D, Structural biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Fragment-Based Discovery of KLK6 and KLK7 Inhibitors.Journal of chemical information and modeling · 2026Article
- A resource-efficient structure-based workflow for fragment progression enables parallel hit discovery and validation of functionally diverse modulators of NCS-1 protein-protein interactions.Chemical science · 2026Article
- Enhancing the Outcome of Crystallographic Fragment Screening by Choosing the Optimal Protein Crystal Form.Small science · 2026Article
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
- Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery.Journal of chemical information and modeling · 2025Article
- Article
- Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain.Communications chemistry · 2025Article
- Virtual fragment screening for DNA repair inhibitors in vast chemical space.Nature communications · 2025Article
- Recent Advances in Automated Structure-Based De Novo Drug Design.Journal of chemical information and modeling · 2024Review
- Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket.Acta crystallographica. Section D, Structural biology · 2024Article
- Crystallographic Fragment Screening on theACS omega · 2023Article
- Fragment Merging Using a Graph Database Samples Different Catalogue Space than Similarity Search.Journal of chemical information and modeling · 2023Article
- Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2.Acta crystallographica. Section D, Structural biology · 2023Article
- Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6.International journal of molecular sciences · 2023Article
- Probing ligand binding of endothiapepsin by `temperature-resolved' macromolecular crystallography.Acta crystallographica. Section D, Structural biology · 2022Article
- Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging.Journal of chemical information and modeling · 2021Article
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Authors and funding
11 authors.
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Abstract
In recent years, crystallographic fragment screening has matured into an almost routine experiment at several modern synchrotron sites. The hits of the screening experiment, i.e. small molecules or fragments binding to the target protein, are revealed along with their 3D structural information. Therefore, they can serve as useful starting points for further structure-based hit-to-lead development. However, the progression of fragment hits to tool compounds or even leads is often hampered by a lack of chemical feasibility. As an attractive alternative, compound analogs that embed the fragment hit structurally may be obtained from commercial catalogs. Here, a workflow is reported based on filtering and assessing such potential follow-up compounds by template docking. This means that the crystallographic binding pose was integrated into the docking calculations as a central starting parameter. Subsequently, the candidates are scored on their interactions within the binding pocket. In an initial proof-of-concept study using five starting fragments known to bind to the aspartic protease endothiapepsin, 28 follow-up compounds were selected using the designed workflow and their binding was assessed by crystallography. Ten of these compounds bound to the active site and five of them showed significantly increased affinity in isothermal titration calorimetry of up to single-digit micromolar affinity. Taken together, this strategy is capable of efficiently evolving the initial fragment hits without major synthesis efforts and with full control by X-ray crystallography.
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