π-Hole Interactions Involving Nitro Aromatic Ligands in Protein Structures

Area of Science:

• Biochemistry
• Chemical Biology
• Structural Biology

Background:

• Noncanonical intermolecular interactions are crucial in molecular recognition.
• Identifying novel interactions aids drug discovery and development.
• Nitro aromatic moieties are present in numerous approved drugs.

Purpose of the Study:

• To investigate the role of π-hole interactions involving nitro aromatic ligands and protein targets.
• To identify and characterize the interaction between the nitro group and protein lone pairs.
• To assess the contribution of these interactions to ligand-protein binding affinity.

Main Methods:

• Analysis of protein data bank (PDB) structures for evidence of π-hole interactions.
• Computational chemistry methods to calculate interaction energies.
• Comparison of binding affinities between nitro aromatic ligands and non-nitro analogues.

Main Results:

• π-hole interactions were identified between the nitro group of ligands and protein lone pairs (water, carbonyls, sulfur).
• Calculations revealed significant interaction energies (approx. -5 kcal/mol) for these π-hole interactions.
• Several examples demonstrated that π-hole interactions enhance ligand binding affinity or inhibitory potency.

Conclusions:

• π-hole interactions involving nitro aromatics are a significant and previously underappreciated force in ligand-protein binding.
• This finding parallels the biological relevance of halogen bonds.
• Understanding these interactions has implications for drug design, particularly for the >50 drugs containing nitro aromatic groups.