Structural Isosteres of Phosphate Groups in the Protein Data Bank

We developed a computational
workflow to mine the Protein Data
Bank for isosteric replacements that exist in different binding site
environments but have not necessarily been identified and exploited
in compound design. Taking phosphate groups as examples, the workflow
was used to construct 157 data sets, each composed of a reference
protein complexed with AMP, ADP, ATP, or pyrophosphate as well other
ligands. Phosphate binding sites appear to have a high hydration content
and large size, resulting in U-shaped bioactive conformations recurrently
found across unrelated protein families. A total of 16 413
replacements were extracted, filtered for a significant structural
overlap on phosphate groups, and sorted according to their SMILES
codes. In addition to the classical isosteres of phosphate, such as
carboxylate, sulfone, or sulfonamide, unexpected replacements that
do not conserve charge or polarity, such as aryl, aliphatic, or positively
charged groups, were found.