期刊
CHEMICAL SCIENCE
卷 9, 期 3, 页码 646-654出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7sc04289b
关键词
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资金
- Swiss National Science Foundation [200020_129935, 200020_146202, R'EQUIP 145023]
- German Academic Exchange Service (DAAD)
- National Science Foundation [CHE-0546311]
- Swiss National Science Foundation (SNF) [200020_129935, 200020_146202] Funding Source: Swiss National Science Foundation (SNF)
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 a-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.
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