Developing high affinity oligosaccharide inhibitors: conformational pre-organization paired with functional group modification

Abstract

Intramolecular tethering combined with functional group modification has been investigated as an approach to design high affinity oligosaccharide ligands. The preceding paper reported successful tethering to constrain a trisaccharide in the conformation of its bound state with an antibody and thereby achieved a 15-fold increase in association constant. Here we report the synthesis of two beta-alanyl tethered derivatives that employ monochlorination and monodeoxygenation strategies to create inhibitors that should enhance the binding affinity of the target molecules by an additional 10-25-fold, provided that free energy changes are additive when tethering is paired with functional group changes. The binding parameters of the new ligands were measured by isothermal titration calorimetry and the results rationalized with molecular dynamics calculations and a simple docking analysis. The data indicate that while the alanine tether is a reasonable method to constrain trisaccharide , free energy gains obtained by pairing it with functional group modification are not additive and in one case counter-productive.

Orthogonal protection of saccharide polyols through solvent-free one-pot sequences based on regioselective silylations

“…The only disappointing result observed in attempted TPDPS protections was the poor yield recorded with glucal 7 (Table 2, entry 13), a surprising outcome which is somehow consistent with the very slow rate observed for the same reaction under standard conditions [39–40]. As already observed for the synthesis of 2 , the herein described conditions for regioselective TBDMS and TBDPS protections entail shorter reaction times than most of the reported protocols in the literature on monosaccharide polyols [14–18 20,41–53]; comparable silylation rates were indeed be found in a few examples, often involving relatively less polar thioaryl glycosides as the substrates and DMF as the solvent [19,54–59]. Having established the scope of TBAB-catalyzed mono silylations with a minimal excess of pyridine, some effort was devoted to ascertain the feasible exploitation of a similar strategy to either regioselective di- O -silylations or the protection of secondary alcohols in absence of primary ones (Table 3).…”

Insights into Modeling Approaches in Chemistry: Assessing Ligand‐Protein Binding Thermodynamics Based on Rigid‐Flexible Model Molecules

“…They suggested that the reorganization of water molecules may also contribute to the binding thermodynamic profiles so that even in such carefully designed model systems, precise quantitative interpretation is difficult. Furthermore, a paper by the same research group [75] described analogs of 7 with some functional groups modified. Although the modification resulted in higher binding affinity, the free energy gains obtained by combining conformational constraints with the functional group changes were shown to be nonadditive and could even be counterproductive.…”