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

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.

A Novel Integrated Way for Deciphering the Glycan Code for the FimH Lectin

“…We additionally computed the same interaction profile for Man and HM (see Figure 3 ). In agreement with previous data [ 9 ], HM engages in van-der-Waals interactions with the tyrosine gate residues (Tyr48, Ile52, and Tyr137). Overall, the HM interaction profile is very similar to that observed of Manα1,2Man, which is in good agreement with the similar interaction energies for both compounds (ΔE int , see Table 2 ).…”

“…Man is much smaller compared to the other ligands and is thus not able to form van-der-Waals interactions with the hydrophobic rim of the binding pocket. Favourable interaction of FimH inhibitors with the tyrosine gate have been shown to significantly contribute to their binding affinity [ 9 ]. The third contribution is the polar solvation energy contributions (ΔG solv POLAR ), which is much higher for Manα1,3Man compared to the other molecules, indicating a higher preference for Manα1,3Man to remain in solution.…”

“…Both dimannoses, although to varying extent, can perform van-der-Waals interactions with Phe1, Ile13, Tyr48, Ile52, Tyr137 and Phe142 (see Figure 3 C). These residues form collar of hydrophobic residues surrounding the FimH binding site [ 9 , 28 , 39 , 40 ]. The crystal structure of FimH with the branched oligomannose-3 [ 36 ] highlights the particular importance of the tyrosine gate formed by the residues Tyr48, Ile52 and Tyr137, for the binding of the mannose rings adjacent to the first mannose ring bound in the pocket (see Figure 3 B).…”

“…The same sugar (α- d -mannose) can be used to inhibit type-1 fimbriae-dependent bacterial adhesion [ 4 ]. Synthetic mannose derivatives, such as the heptyl α- d -mannopyranoside, have shown to inhibit FimH adhesin even more effectively [ 5 , 6 , 7 , 8 , 9 ]. The need for such compounds is high as FimH-mediated binding of E. coli is of central importance in a variety of diseases including Crohn’s Disease (CD), urinary tract infections (UTI), enteritis, diarrhoea, sepsis and meningitis [ 10 ].…”

Molecular Modeling in Drug Design

“…Two of the Reviews discuss the application of a combination of molecular docking and MD simulation-based approaches for target-based drug design. Krammer and co-workers [8] review the design of non-antibiotic anti-adhesives against the bacterial adhesin FimH, emphasizing the significance of the incorporation of the dynamic aspects of ligand-target interactions in drug design studies. Likewise, Ferraro and Colombo [9], in their Perspective, show examples of how MD simulations, in concert with screening approaches, can help in tackling challenging protein–protein interactions and designing therapeutic small molecules that inhibit such interactions.…”