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Quantum mechanical studies of lincosamides

Lincosamides are a class of antibiotics used both in clinical and veterinary practice for a wide range of pathogens. This group of drugs inhibits the activity of the bacterial ribosome by binding to the 23S RNA of the large ribosomal subunit and blocking protein synthesis. Currently, three X-ray str...

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Autores principales: Kulczycka-Mierzejewska, Katarzyna, Trylska, Joanna, Sadlej, Joanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer-Verlag 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360846/
https://www.ncbi.nlm.nih.gov/pubmed/22116607
http://dx.doi.org/10.1007/s00894-011-1272-4
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author Kulczycka-Mierzejewska, Katarzyna
Trylska, Joanna
Sadlej, Joanna
author_facet Kulczycka-Mierzejewska, Katarzyna
Trylska, Joanna
Sadlej, Joanna
author_sort Kulczycka-Mierzejewska, Katarzyna
collection PubMed
description Lincosamides are a class of antibiotics used both in clinical and veterinary practice for a wide range of pathogens. This group of drugs inhibits the activity of the bacterial ribosome by binding to the 23S RNA of the large ribosomal subunit and blocking protein synthesis. Currently, three X-ray structures of the ribosome in complex with clindamycin are available in the Protein Data Bank, which reveal that there are two distinct conformations of the pyrrolidinyl propyl group of the bound clindamycin. In this work, we used quantum mechanical methods to investigate the probable conformations of clindamycin in order to explain the two binding modes in the ribosomal 23S RNA. We studied three lincosamide antibiotics: clindamycin, lincomycin, and pirlimycin at the B3LYP level with the 6-31G(**) basis set. The focus of our work was to connect the conformational landscape and electron densities of the two clindamycin conformers found experimentally with their physicochemical properties. For both functional conformers, we applied natural bond orbital (NBO) analysis and the atoms in molecules (AIM) theory, and calculated the NMR parameters. Based on the results obtained, we were able to show that the structure with the intramolecular hydrogen bond C=O…H–O is the most stable conformer of clindamycin. The charge transfer between the pyrrolidine-derivative ring and the six-atom sugar (methylthiolincosamide), which are linked via an amide bond, was found to be the dominant factor influencing the high stability of this conformer. [Figure: see text]
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spelling pubmed-33608462012-06-13 Quantum mechanical studies of lincosamides Kulczycka-Mierzejewska, Katarzyna Trylska, Joanna Sadlej, Joanna J Mol Model Original Paper Lincosamides are a class of antibiotics used both in clinical and veterinary practice for a wide range of pathogens. This group of drugs inhibits the activity of the bacterial ribosome by binding to the 23S RNA of the large ribosomal subunit and blocking protein synthesis. Currently, three X-ray structures of the ribosome in complex with clindamycin are available in the Protein Data Bank, which reveal that there are two distinct conformations of the pyrrolidinyl propyl group of the bound clindamycin. In this work, we used quantum mechanical methods to investigate the probable conformations of clindamycin in order to explain the two binding modes in the ribosomal 23S RNA. We studied three lincosamide antibiotics: clindamycin, lincomycin, and pirlimycin at the B3LYP level with the 6-31G(**) basis set. The focus of our work was to connect the conformational landscape and electron densities of the two clindamycin conformers found experimentally with their physicochemical properties. For both functional conformers, we applied natural bond orbital (NBO) analysis and the atoms in molecules (AIM) theory, and calculated the NMR parameters. Based on the results obtained, we were able to show that the structure with the intramolecular hydrogen bond C=O…H–O is the most stable conformer of clindamycin. The charge transfer between the pyrrolidine-derivative ring and the six-atom sugar (methylthiolincosamide), which are linked via an amide bond, was found to be the dominant factor influencing the high stability of this conformer. [Figure: see text] Springer-Verlag 2011-11-25 2012 /pmc/articles/PMC3360846/ /pubmed/22116607 http://dx.doi.org/10.1007/s00894-011-1272-4 Text en © The Author(s) 2011 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Original Paper
Kulczycka-Mierzejewska, Katarzyna
Trylska, Joanna
Sadlej, Joanna
Quantum mechanical studies of lincosamides
title Quantum mechanical studies of lincosamides
title_full Quantum mechanical studies of lincosamides
title_fullStr Quantum mechanical studies of lincosamides
title_full_unstemmed Quantum mechanical studies of lincosamides
title_short Quantum mechanical studies of lincosamides
title_sort quantum mechanical studies of lincosamides
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360846/
https://www.ncbi.nlm.nih.gov/pubmed/22116607
http://dx.doi.org/10.1007/s00894-011-1272-4
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