Acid Versus Amide-Facts and Fallacies: A Case Study in Glycomimetic Ligand Design.

ABSTRACT: The replacement of ionizable functional groups that are predominantly charged at physiological pH with neutral bioisosteres is a common strategy in medicinal chemistry; however, its impact on binding affinity is often context-dependent. Here, we investigated a series of amide derivatives of a glycomimetic E-selectin ligand, in which the carboxylate group of the lead compound is substituted with a range of amide and isosteric analogs. Despite the expected loss of the salt-bridge interaction with Arg97, several amides retained or even improved the binding affinity. Co-crystal structures revealed conserved binding poses across the series, with consistent interactions involving the carbonyl oxygen of the amide and the key residues Tyr48 and Arg97. High-level quantum chemical calculations ruled

SUBMITTER: Smiesko M 

PROVIDER: S-EPMC12736226 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature