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.
Molecules. 2018 Jul 5;23(7):1641. doi: 10.3390/molecules23071641.
Located at the tip of type I fimbria of , 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.
位于 I 型菌毛顶端的细菌黏附素 FimH 通过特异性结合宿主细胞外壁上高度甘露糖化糖蛋白，负责细菌与（人类）宿主的附着。黏附是细菌感染的必要早期步骤，而对该过程的特异性抑制代表了一种有价值的抗生素治疗替代途径，因为这种抗黏附药物是非侵入性的，因此不太可能诱导细菌产生耐药性。目前具有最高 FimH 亲和力的可用抗黏附剂的亲和力仍在纳摩尔范围内。开发具有更高亲和力的 FimH 抑制剂的前提是对 FimH-抑制剂复合物形成有分子上的理解。通过结合几种分子模拟和传统实验技术，可以实现对形成过程的最新见解。这篇综述总结了分子模拟如何有助于当前对 FimH 分子功能的认识，以及动力学在抑制剂结合过程中的重要性，并强调了在（未来）药物设计研究中纳入动态方面的重要性。
