Issue 3, 2018

The price of flexibility – a case study on septanoses as pyranose mimetics

Abstract

Seven-membered ring mimetics of mannose were studied as ligands for the mannose-specific bacterial lectin FimH, which plays an essential role in the first step of urinary tract infections (UTI). A competitive binding assay and isothermal titration calorimetry (ITC) experiments indicated an approximately ten-fold lower affinity for the seven-membered ring mannose mimetic 2-O-n-heptyl-1,6-anhydro-D-glycero-D-galactitol (7) compared to n-heptyl α-D-mannopyranoside (2), resulting exclusively from a loss of conformational entropy. Investigations by solution NMR, X-ray crystallography, and molecular modeling revealed that 7 establishes a superimposable H-bond network compared to mannoside 2, but at the price of a high entropic penalty due to the loss of its pronounced conformational flexibility. These results underscore the importance of having access to the complete thermodynamic profile of a molecular interaction to “rescue” ligands from entropic penalties with an otherwise perfect fit to the protein binding site.

Graphical abstract: The price of flexibility – a case study on septanoses as pyranose mimetics

Supplementary files

Article information

Article type
Edge Article
Submitted
02 Oct 2017
Accepted
07 Nov 2017
First published
08 Nov 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 646-654

The price of flexibility – a case study on septanoses as pyranose mimetics

C. P. Sager, B. Fiege, P. Zihlmann, R. Vannam, S. Rabbani, R. P. Jakob, R. C. Preston, A. Zalewski, T. Maier, M. W. Peczuh and B. Ernst, Chem. Sci., 2018, 9, 646 DOI: 10.1039/C7SC04289B

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