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.