We present an analysis of the chemical fragments from lead-like ligands in the Protein Data Bank (PDB) that form hydrogen bonds to the side chains of Asp, Glu, Arg, and His, which are the most common residues found in ligand binding sites. A fragment is defined as the largest ring assembly containing the atoms involved in hydrogen bonding. In total, 462 fragments were found in 2038 ligands from over 8000 protein-ligand structures in the PDB. The results show which fragments have a higher propensity for interaction with specific side chains. Some fragments interact with Asp but not with Glu, and vice versa, despite these side chains sharing the same chemical moiety. Arg side chains form hydrogen bonds almost exclusively with O-mediated ligands, and the fragments are the most diverse. Hydrogen bond distances from the imidazole of His showed a wider range than the other three amino acids.