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Molecules 2018, 23(7), 1641; https://doi.org/10.3390/molecules23071641

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

Unite de Glycobiologie Structurale et Fonctionnelle, UMR 8576 of the Centre National de la Recherche Scientifique and the University of Lille, 50 Avenue de Halley, 59658 Villeneuve d’Ascq, France
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Academic Editors: Rebecca Wade and Outi Salo-Ahen
Received: 10 June 2018 / Revised: 29 June 2018 / Accepted: 2 July 2018 / Published: 5 July 2018
(This article belongs to the Special Issue Molecular Modeling in Drug Design)
Full-Text   |   PDF [5287 KB, uploaded 5 July 2018]   |  

Abstract

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. View Full-Text
Keywords: adhesion; FimH; rational drug design; molecular dynamics; molecular docking; ligand binding adhesion; FimH; rational drug design; molecular dynamics; molecular docking; ligand binding
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Krammer, E.-M.; de Ruyck, J.; Roos, G.; Bouckaert, J.; Lensink, M.F. Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH. Molecules 2018, 23, 1641.

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