Dokument: Structural and dynamic insights into oxazolidinone binding, selectivity and resistance to the large ribosomal subunit
| Titel: | Structural and dynamic insights into oxazolidinone binding, selectivity and resistance to the large ribosomal subunit | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=45022 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20180306-094115-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr. Saini, Jagmohan [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Gohlke, Holger [Gutachter] Prof. Dr. Steger, Gerhard [Gutachter] | |||||||
| Stichwörter: | Ribosomes, Antibiotics, Free energy calculations, | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | The ribosome is a ribozyme that catalysis the mRNA-directed protein synthesis. Prokaryotic ribosomes are composed of two unequal subunits (30S and 50S). These subunits contain several important functional sites that act as potential antibiotic targets. One of them is the peptidyl transferase center (PTC) located in the 50S large ribosomal subunit. The PTC is a target for various antibiotics used in the clinics such as erythromycin, clindamycin, and chloramphenicol. The ever increasing emergence of multi-drug-resistant bacteria warrants the need to continuously identify new antibiotics.
Oxazolidinones represent one of the few new chemical classes of antibiotics that have been introduced in the clinics over the past 40 years. Linezolid, the only member of this class approved by the FDA, shows excellent activity against major Gram-positive bacteria. The available co-crystal structures of linezolid with the large ribosomal subunit of Deinococcus radiodurans (D50S) and Haloarcula marismortui (H50S) provide static views of the binding processes but do not reveal the dynamics and energetics involved with antibiotics binding [24, 25]. In order to understand determinants of binding and factors that give rise to selectivity and the resistance development due to mutations for the first time, computational expensive molecular dynamics (MD) simulations in combination with MM-PBSA free energy calculations of oxazolidinones; (linezolid, radezolid and the structurally related drug rivaroxaban) bound to D50S and H50S were performed. Our results provide a remarkably good agreement of the computed relative binding free energy with selectivity data available from experiment for linezolid. Moreover, structural data as well as energetic analysis shows that binding of radezolid to H50S is more favorable over D50S. Furthermore, the structurally related rivaroxaban does not bind to the ribosome reflected in its displacement from initial binding position as well as considerable positive ΔGeffective. In line with literature reports, the structural decomposition identifies nucleotides 2055 and 2572 to be most important for antibiotic selectivity. With respect to the development of linezolid resistance, the analysis shows an unstable binding mode of linezolid in H50Smut over stable binding modes in H50Swt and D50S.The structural and energetic analysis identify U2504 and C2452 as spearheads that exert the most immediate effect on linezolid binding due to the remote double mutation. The results presented here are in-line with modifications of antibiotics belonging to the oxazolidinone class in clinical trials and FDA approved antibiotics binding to the ribosomal subunit. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 06.03.2018 | |||||||
| Dateien geändert am: | 06.03.2018 | |||||||
| Promotionsantrag am: | 05.02.2018 | |||||||
| Datum der Promotion: | 05.03.2018 |
