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

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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

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Publication details

The article was received on 02 Oct 2017, accepted on 07 Nov 2017 and first published on 08 Nov 2017


Article type: Edge Article
DOI: 10.1039/C7SC04289B
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY-NC license
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    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, Advance Article , DOI: 10.1039/C7SC04289B

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