π‐Hole Interactions Involving Nitro Aromatic Ligands in Protein Structures

Studying noncanonical intermolecular interactions between a ligand and a protein constitutes an emerging research field. Identifying synthetically accessible molecular fragments that can engage in intermolecular interactions is a key objective in this area. Here, it is shown that so‐called “π‐hole interactions” are present between the nitro moiety in nitro aromatic ligands and lone pairs within protein structures (water and protein carbonyls and sulfurs). Ample structural evidence was found in a PDB analysis and computations reveal interaction energies of about −5 kcal mol(−1) for ligand–protein π‐hole interactions. Several examples are highlighted for which a π‐hole interaction is implicated in the superior binding affinity or inhibition of a nitro aromatic ligand versus a similar non‐nitro analogue. The discovery that π‐hole interactions with nitro aromatics are significant within protein structures parallels the finding that halogen bonds are biologically relevant. This has implications for the interpretation of ligand–protein complexation phenomena, for example, involving the more than 50 approved drugs that contain a nitro aromatic moiety.