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In this work, 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, see workflow in Figure 1. In addition to classical isosteres of phosphate, we found unexpected types of replacements that do not conserve charge or polarity, for example phosphate replaced by aliphatic groups, phenyl, or carbamoyl groups. The structural mechanism involved in structural isosteres appears varied: New interactions may be created, water molecules are important, in some case ion plays a role, and of course large and small conformational changes do occur at the binding sites. This study has implications both in the field of medicinal chemistry, i.e. it expands our knowledge of structural isosteres, and in the field of chemoinformatics, since our results have implications with respect to the definitions of chemical similarity.