5cgb

Publication Abstract from PubMed

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 alpha-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.

The price of flexibility - a case study on septanoses as pyranose mimetics.,Sager CP, Fiege B, Zihlmann P, Vannam R, Rabbani S, Jakob RP, Preston RC, Zalewski A, Maier T, Peczuh MW, Ernst B Chem Sci. 2017 Nov 8;9(3):646-654. doi: 10.1039/c7sc04289b. eCollection 2018 Jan , 21. PMID:29629131^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.