Journal article
The price of flexibility - a case study on septanoses as pyranose mimetics.
- Sager CP University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- Fiege B University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- Zihlmann P University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- Vannam R Department of Chemistry , University of Connecticut , 55 N. Eagleville Road U3060, Storrs , CT , 06279 USA . Email: mark.peczuh@uconn.edu.
- Rabbani S University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- Jakob RP University of Basel , Biozentrum: Focal Area Structural Biology , Klingelbergstrasse 70 , 4056 Basel , Switzerland.
- Preston RC University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- Zalewski A University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- Maier T University of Basel , Biozentrum: Focal Area Structural Biology , Klingelbergstrasse 70 , 4056 Basel , Switzerland.
- Peczuh MW Department of Chemistry , University of Connecticut , 55 N. Eagleville Road U3060, Storrs , CT , 06279 USA . Email: mark.peczuh@uconn.edu.
- Ernst B University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email: beat.ernst@unibas.ch.
- 2018-04-10
Published in:
- Chemical science. - 2018
English
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1039/c7sc04289b
- PMID 29629131
- Persistent URL
- https://sonar.ch/global/documents/263982
Statistics
Document views: 14
File downloads: