Discovery of Fragment Molecules That Bind the Human Peroxiredoxin 5 Active Site
| Autor: | Isabelle Krimm, Sarah Barelier, Dominique Linard, Bernard Knoops, André Clippe, Jean-Marc Lancelin, Julien Pons |
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| Přispěvatelé: | Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chimie Provence (LCP), Université de Provence - Aix-Marseille 1-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Institut des Sciences de la Vie, Criblage de fragment, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Protein Conformation lcsh:Medicine [CHIM.THER]Chemical Sciences/Medicinal Chemistry Crystallography X-Ray Ligands Protein structure Catalytic Domain Humans Cysteine Binding site lcsh:Science Biochemistry/Biomacromolecule-Ligand Interactions Multidisciplinary Binding Sites biology Chemistry lcsh:R Active site Peroxiredoxins respiratory system Small molecule Enzyme structure Kinetics Biochemistry Models Chemical Peroxidases Biochemistry/Bioinformatics Docking (molecular) biology.protein lcsh:Q Biochemistry/Drug Discovery Peroxiredoxin Protein ligand Protein Binding Research Article |
| Zdroj: | PLoS ONE PLoS ONE, 2010, 5 (3), pp.e9744. ⟨10.1371/journal.pone.0009744⟩ PLoS ONE, Vol 5, Iss 3, p e9744 (2010) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0009744⟩ |
| Popis: | The search for protein ligands is a crucial step in the inhibitor design process. Fragment screening represents an interesting method to rapidly find lead molecules, as it enables the exploration of a larger portion of the chemical space with a smaller number of compounds as compared to screening based on drug-sized molecules. Moreover, fragment screening usually leads to hit molecules that form few but optimal interactions with the target, thus displaying high ligand efficiencies. Here we report the screening of a homemade library composed of 200 highly diverse fragments against the human Peroxiredoxin 5 protein. Peroxiredoxins compose a family of peroxidases that share the ability to reduce peroxides through a conserved cysteine. The three-dimensional structures of these enzymes ubiquitously found throughout evolution have been extensively studied, however, their biological functions are still not well understood and to date few inhibitors have been discovered against these enzymes. Six fragments from the library were shown to bind to the Peroxiredoxin 5 active site and ligand-induced chemical shift changes were used to drive the docking of these small molecules into the protein structure. The orientation of the fragments in the binding pocket was confirmed by the study of fragment homologues, highlighting the role of hydroxyl functions that hang the ligands to the Peroxiredoxin 5 protein. Among the hit fragments, the small catechol molecule was shown to significantly inhibit Peroxiredoxin 5 activity in a thioredoxin peroxidase assay. This study reports novel data about the ligand-Peroxiredoxin interactions that will help considerably the development of potential Peroxiredoxin inhibitors. |
| Databáze: | OpenAIRE |
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