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Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH

Located at the tip of type I fimbria of Escherichia coli, the bacterial adhesin FimH is responsible for the attachment of the bacteria to the (human) host by specifically binding to highly-mannosylated glycoproteins located on the exterior of the host cell wall. Adhesion represents a necessary early...

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Autores principales: Krammer, Eva-Maria, de Ruyck, Jerome, Roos, Goedele, Bouckaert, Julie, Lensink, Marc F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099838/
https://www.ncbi.nlm.nih.gov/pubmed/29976867
http://dx.doi.org/10.3390/molecules23071641
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author Krammer, Eva-Maria
de Ruyck, Jerome
Roos, Goedele
Bouckaert, Julie
Lensink, Marc F.
author_facet Krammer, Eva-Maria
de Ruyck, Jerome
Roos, Goedele
Bouckaert, Julie
Lensink, Marc F.
author_sort Krammer, Eva-Maria
collection PubMed
description Located at the tip of type I fimbria of Escherichia coli, the bacterial adhesin FimH is responsible for the attachment of the bacteria to the (human) host by specifically binding to highly-mannosylated glycoproteins located on the exterior of the host cell wall. Adhesion represents a necessary early step in bacterial infection and specific inhibition of this process represents a valuable alternative pathway to antibiotic treatments, as such anti-adhesive drugs are non-intrusive and are therefore unlikely to induce bacterial resistance. The currently available anti-adhesives with the highest affinities for FimH still feature affinities in the nanomolar range. A prerequisite to develop higher-affinity FimH inhibitors is a molecular understanding of the FimH-inhibitor complex formation. The latest insights in the formation process are achieved by combining several molecular simulation and traditional experimental techniques. This review summarizes how molecular simulation contributed to the current knowledge of the molecular function of FimH and the importance of dynamics in the inhibitor binding process, and highlights the importance of the incorporation of dynamical aspects in (future) drug-design studies.
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spelling pubmed-60998382018-11-13 Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH Krammer, Eva-Maria de Ruyck, Jerome Roos, Goedele Bouckaert, Julie Lensink, Marc F. Molecules Review Located at the tip of type I fimbria of Escherichia coli, the bacterial adhesin FimH is responsible for the attachment of the bacteria to the (human) host by specifically binding to highly-mannosylated glycoproteins located on the exterior of the host cell wall. Adhesion represents a necessary early step in bacterial infection and specific inhibition of this process represents a valuable alternative pathway to antibiotic treatments, as such anti-adhesive drugs are non-intrusive and are therefore unlikely to induce bacterial resistance. The currently available anti-adhesives with the highest affinities for FimH still feature affinities in the nanomolar range. A prerequisite to develop higher-affinity FimH inhibitors is a molecular understanding of the FimH-inhibitor complex formation. The latest insights in the formation process are achieved by combining several molecular simulation and traditional experimental techniques. This review summarizes how molecular simulation contributed to the current knowledge of the molecular function of FimH and the importance of dynamics in the inhibitor binding process, and highlights the importance of the incorporation of dynamical aspects in (future) drug-design studies. MDPI 2018-07-05 /pmc/articles/PMC6099838/ /pubmed/29976867 http://dx.doi.org/10.3390/molecules23071641 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Krammer, Eva-Maria
de Ruyck, Jerome
Roos, Goedele
Bouckaert, Julie
Lensink, Marc F.
Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH
title Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH
title_full Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH
title_fullStr Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH
title_full_unstemmed Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH
title_short Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH
title_sort targeting dynamical binding processes in the design of non-antibiotic anti-adhesives by molecular simulation—the example of fimh
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099838/
https://www.ncbi.nlm.nih.gov/pubmed/29976867
http://dx.doi.org/10.3390/molecules23071641
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