Similarity searching using fingerprints of molecular fragments involved in protein-ligand interactions.

To incorporate protein-ligand interaction information into conventional two-dimensional (2D) fingerprint searching, interacting fragments of active compounds were extracted from X-ray structures of protein-ligand complexes and encoded as structural key-type fingerprints. Similarity search calculations with fingerprints derived from interacting fragments were compared to fingerprints of complete ligands and control fragments. In these calculations, fingerprints of interacting fragments produced significantly higher compound recall than other fingerprints. These results indicate that ligand fragments involved in protein-ligand interactions carry much activity-specific chemical information that can be exploited in similarity searching without explicitly accounting for interaction information.