Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening
| Autor: | Jean-Yves Springael, Didier Rognan, Marc Parmentier, Jean-Luc Galzi, Esther Kellenberger, Muriel Hachet-Haas |
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| Přispěvatelé: | Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Faculteit Toegepaste Economische Wetenschappen (TEW), University of Antwerp (UA), Agence Universitaire de la Francophonie (AUF), Récepteurs et protéines membranaires (RPM), Centre National de la Recherche Scientifique (CNRS), Pharmacochimie de la communication cellulaire (PCC), Instiitut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université de Bruxelles, Université libre de Bruxelles (ULB), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS) |
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Pyrrolidines Chemokine receptor CCR5 MESH: Sequence Homology Amino Acid MESH: Piperazines Quantitative Structure-Activity Relationship [CHIM.THER]Chemical Sciences/Medicinal Chemistry MESH: Amino Acid Sequence MESH: Receptors CCR5 01 natural sciences Piperazines MESH: Protein Structure Tertiary Piperidines Drug Discovery Receptor 0303 health sciences MESH: Quantitative Structure-Activity Relationship biology [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Molecular Structure Chemistry virus diseases [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences 3. Good health Pyridazines MESH: Quinazolines MESH: Piperidines CCR5 Receptor Antagonists Molecular Medicine Pharmacophore [CHIM.CHEM]Chemical Sciences/Cheminformatics MESH: Models Molecular Agonist Receptors CCR5 Stereochemistry medicine.drug_class In silico MESH: Molecular Structure Molecular Sequence Data CCR5 receptor antagonist Computational biology 03 medical and health sciences MESH: Pyridazines medicine Amino Acid Sequence 030304 developmental biology Virtual screening MESH: Molecular Sequence Data MESH: Pyrrolidines Sequence Homology Amino Acid Triazoles 0104 chemical sciences Protein Structure Tertiary 010404 medicinal & biomolecular chemistry MESH: Triazoles Docking (molecular) biology.protein Quinazolines |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2007, 50 (6), pp.1294-303. ⟨10.1021/jm061389p⟩ Journal of Medicinal Chemistry, American Chemical Society, 2007, 50 (6), pp.1294-1303. ⟨10.1021/jm061389p⟩ |
| ISSN: | 0022-2623 1520-4804 |
| Popis: | International audience; A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its alpha-helix bundle and to distinguish known CCR5 antagonists from randomly chosen drug-like decoys. In silico screening of a library of 1.6 million commercially available compounds against the CCR5 model by sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit list of 59 compounds, out of which 10 exhibited a detectable binding affinity to the CCR5 receptor. Unexpectedly, most binders tested in a functional assay were shown to be agonists of the CCR5 receptor. A follow-up database query based on similarity to the most potent binders identified three new CCR5 agonists. Despite a moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection. |
| Databáze: | OpenAIRE |
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