Identified Isosteric Replacements of Ligands’ Glycosyl Domain by Data Mining

[Image: see text] Biologically equivalent replacements of key moieties in molecules rationalize scaffold hopping, patent busting, or R-group enumeration. Yet, this information may depend upon the expert-defined space, and might be subjective and biased toward the chemistries they get used to. Most importantly, these practices are often informatively incomplete since they are often compromised by a try-and-error cycle, and although they depict what kind of substructures are suitable for the replacement occurrence, they fail to explain the driving forces to support such interchanges. The protein data bank (PDB) encodes a receptor-ligand interaction pattern and could be an optional source to mine structural surrogates. However, manual decoding of PDB has become almost impossible and redundant to excavate the bioisosteric know-how. Therefore, a text parsing workflow has been developed to automatically extract the local structural replacement of a specific structure from PDB by finding spatial and steric interaction overlaps between the fragments in endogenous ligands and particular ligand fragments. Taking the glycosyl domain for instance, a total of 49 520 replacements that overlap on nucleotide ribose were identified and categorized based on their SMILE codes. A predominately ring system, such as aliphatic and aromatic rings, was observed; yet, amide and sulfonamide replacements also occur. We believe these findings may enlighten medicinal chemists on the structure design and optimization of ligands using the bioisosteric replacement strategy.