A survey of the role of nitrile groups in protein–ligand interactions

In classical medicinal chemistry, nitrile groups were commonly considered as bioisosteres of carbonyl, hydroxyl and carboxyl groups, as well as halogen atoms. However, there is a lack of in-depth understanding about the structural and energetic characteristics of nitrile groups in protein-ligand interactions. Here, we have surveyed the Protein Data Bank and ChEMBL databases with the goal of characterizing such protein-ligand interactions for nitrile-containing compounds. We discuss the versatile roles of nitrile groups in improving binding affinities, and give special attention to examples of displacing and mimicking binding-site waters by nitrile groups. We expect that this review article will further inspire medicinal chemists to exploit nitrile groups rationally in structure-based drug design.