The price of flexibility – a case study on septanoses as pyranose mimetics† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc04289b

Interacting with lectins, mannose can be mimicked with seven-membered ring analogues but at the price of a substantial entropy penalty. 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.