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 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.