Insights into molecular mechanisms of drug metabolism dysfunction of human CYP2C9*30
| العنوان: | Insights into molecular mechanisms of drug metabolism dysfunction of human CYP2C9*30 |
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| المؤلفون: | Céline M. Labbé, Charline Fagnen, Paula Homem-de-Mello, Maxime Louet, Cassiano Minoru Aono, Maria A. Miteva, Bruno O. Villoutreix |
| المساهمون: | Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal do ABC (UFABC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), Universidade Federal do ABC = Federal University of ABC = Université Fédérale de l'ABC [Brazil] (UFABC), HAL UPMC, Gestionnaire, ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-16-CE18-0025,ToxME,ToxME: une approche in silico intégrative pour comprendre des mécanismes de polymorphisme et des effets secondaires de médicaments liés a des enzymes du métabolisme(2016) |
| المصدر: | PLoS ONE PLoS ONE, Public Library of Science, 2018, 13 (5), pp.e0197249. ⟨10.1371/journal.pone.0197249⟩ PLoS ONE, 2018, 13 (5), pp.e0197249. ⟨10.1371/journal.pone.0197249⟩ PLoS ONE, Vol 13, Iss 5, p e0197249 (2018) |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Pharmacogenomic Variants, Protein Conformation, lcsh:Medicine, Plasma protein binding, Molecular Dynamics, Biochemistry, chemistry.chemical_compound, Database and Informatics Methods, Protein Structure Databases, 0302 clinical medicine, Protein structure, Computational Chemistry, Drug Metabolism, Biochemical Simulations, Medicine and Health Sciences, Macromolecular Structure Analysis, Post-Translational Modification, lcsh:Science, Heme, chemistry.chemical_classification, Multidisciplinary, Crystallography, biology, Molecular Structure, Physics, Prodrug, Condensed Matter Physics, Chemistry, 030220 oncology & carcinogenesis, Physical Sciences, Crystal Structure, Protein Binding, Research Article, Protein Structure, Molecular Dynamics Simulation, Research and Analysis Methods, Catalysis, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Solid State Physics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Pharmacokinetics, Molecular Biology, Cytochrome P-450 CYP2C9, Pharmacology, Chemical Physics, lcsh:R, Substrate (chemistry), Active site, Biology and Life Sciences, Computational Biology, Proteins, 030104 developmental biology, Enzyme, Biological Databases, chemistry, Mutation, Biophysics, biology.protein, lcsh:Q, Drug metabolism, Metabolism, Inborn Errors |
| الوصف: | International audience; Cytochrome P450 2C9 (CYP2C9) metabolizes about 15% of clinically administrated drugs. The allelic variant CYP2C9*30 (A477T) is associated to diminished response to the antihy-pertensive effects of the prodrug losartan and affected metabolism of other drugs. Here, we investigated molecular mechanisms involved in the functional consequences of this amino-acid substitution. Molecular dynamics (MD) simulations performed for the active species of the enzyme (heme in the Compound I state), in the apo or substrate-bound state, and binding energy analyses gave insights into altered protein structure and dynamics involved in the defective drug metabolism of human CYP2C9.30. Our data revealed an increased rigidity of the key Substrate Recognition Sites SRS1 and SRS5 and shifting of the β turn 4 of SRS6 toward the helix F in CYP2C9.30. Channel and binding substrate dynamics analyses showed altered substrate channel access and active site accommodation. These conformational and dynamic changes are believed to be involved in the governing mechanism of the reduced catalytic activity. An ensemble of representative conformations of the WT and A477T mutant properly accommodating drug substrates were identified, those structures can be used for prediction of new CYP2C9 and CYP2C9.30 substrates and drug-drug interactions. |
| وصف الملف: | application/pdf |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::566ec0fdece7f695a389d4bf0ce01d6bTest https://pubmed.ncbi.nlm.nih.gov/29746595Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....566ec0fdece7f695a389d4bf0ce01d6b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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