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

Sager, Christoph P. and Fiege, Brigitte and Zihlmann, Pascal and Vannam, Raghu and Rabbani, Said and Jakob, Roman P. and Preston, Roland C. and Zalewski, Adam and Maier, Timm and Peczuh, Mark W. and Ernst, Beat. (2018) The price of flexibility - a case study on septanoses as pyranose mimetics. Chemical Science, 9 (3). pp. 646-654.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Maier, Timm and Ernst, Beat and Sager, Christoph and Fiege, Brigitte and Zihlmann, Pascal and Rabbani, Said and Jakob, Roman Peter and Preston, Roland and Zalewski, Adam
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Royal Society of Chemistry
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2023 13:47
Deposited On:06 Feb 2018 17:58

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