?-Hole Interactions Involving Nitro Aromatic Ligands in Protein Structures.

ABSTRACT: 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 "?-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 ?-hole interactions. Several examples are highlighted for which a ?-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 ?-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.

SUBMITTER: Bauza A 

PROVIDER: S-EPMC6856858 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature