ArticleActa crystallographica. Section F, Structural biology communications2016
Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library.
Article in Acta crystallographica. Section F, Structural biology communications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 38 citations in OpenAlex.
- Article
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- Probing ligand binding of endothiapepsin by `temperature-resolved' macromolecular crystallography.Acta crystallographica. Section D, Structural biology · 2022Article
- Fast fragment- and compound-screening pipeline at the Swiss Light Source.Acta crystallographica. Section D, Structural biology · 2022Article
- Targeting the N-Terminus Domain of the Coronavirus Nucleocapsid Protein Induces Abnormal Oligomerization via Allosteric Modulation.Frontiers in molecular biosciences · 2022Article
- Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) fromPharmaceuticals (Basel, Switzerland) · 2021Article
- Substrate binding modes of purine and pyrimidine nucleotides to human ecto-5'-nucleotidase (CD73) and inhibition by their bisphosphonic acid derivatives.Purinergic signalling · 2021Article
- Additive CHARMM36 Force Field for Nonstandard Amino Acids.Journal of chemical theory and computation · 2021Article
- Crystallographic fragment screening-based study of a novel FAD-dependent oxidoreductase from Chaetomium thermophilum.Acta crystallographica. Section D, Structural biology · 2021Article
- Uncertainty in protein-ligand binding constants: asymmetric confidence intervals versus standard errors.European biophysics journal : EBJ · 2021Article
- FragMAX: the fragment-screening platform at the MAX IV Laboratory.Acta crystallographica. Section D, Structural biology · 2020Article
- Paired refinement under the control ofIUCrJ · 2020Article
- Establishing Trypanosoma cruzi farnesyl pyrophosphate synthase as a viable target for biosensor driven fragment-based lead discovery.Protein science : a publication of the Protein Society · 2020Article
- A Proof-of-Concept Fragment Screening of a Hit-Validated 96-Compounds Library against Human Carbonic Anhydrase II.Biomolecules · 2020Article
- Protein X-ray Crystallography and Drug Discovery.Molecules (Basel, Switzerland) · 2020Review
- Fragments as Novel Starting Points for tRNA-Guanine Transglycosylase Inhibitors Found by Alternative Screening Strategies.ChemMedChem · 2020Article
- Influence of Catecholamines (Epinephrine/Norepinephrine) on Biofilm Formation and Adhesion in Pathogenic and Probiotic Strains ofFrontiers in microbiology · 2020Article
- MXCuBE2: the dawn of MXCuBE Collaboration.Journal of synchrotron radiation · 2019Article
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Authors and funding
11 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other fragment libraries and considering that no pre-screening was performed, this hit rate is remarkably high. This demonstrates the general suitability of the selected compounds for an initial fragment-screening campaign. The library composition, experimental considerations and time requirements for a complete crystallographic fragment-screening campaign are discussed as well as the nine fully refined obtained endothiapepsin-fragment structures. While most of the fragments bind close to the catalytic centre of endothiapepsin in poses that have been observed previously, two fragments address new sites on the protein surface. ITC measurements show that the fragments bind to endothiapepsin with millimolar affinity.
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