π‐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 “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.

Bulk polarity of 3,5,7-trinitro-1-azaadamantane mediated by asymmetric NO2(lone pair)...NO2(π-hole) supramolecular bonding

“…The energy of such bonding is superior, by ca 5-8 kJ mol À1 , to the single C-HÁ Á ÁO hydrogen bonds of aliphatic donors and nitro acceptors (Type 2). The latter is similar to the energy pattern for 2,4dinitro-2,4-hexadiene (Bauzá et al, 2017), whereas the bonding of nitro ligands in protein structures suggests even larger differences, of up to 17 kJ mol À1 (Bauzá et al, 2019). With a lack of stronger intermolecular interactions, shapecomplementary stacks of pyramidal molecules and the mutual interactions of nitro groups provide the main motifs of the crystal packing, which results in the polar molecular arrangement.…”

π-Hole Interactions with Various Nitro Compounds Relevant for Medicine: DFT Calculations and Surveys of the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB)

“…11 The potential of this hole depends largely on the nature of R, but can always be amplified when electron density is withdrawn from the Oatoms. 6c,11a,b, 12 Indeed, even nitrate anions can bear a -hole when the negative charge is sufficiently spread out over a larger area through hydrogen bonding 13 or coordination to a metal. 14 Nitrate esters 11b and nitro aromatics 12 have been highlighted as particularly interesting nitro compounds as they are found as ligands in protein structures and are used in important medicine.…”

“…6c,11a,b, 12 Indeed, even nitrate anions can bear a -hole when the negative charge is sufficiently spread out over a larger area through hydrogen bonding 13 or coordination to a metal. 14 Nitrate esters 11b and nitro aromatics 12 have been highlighted as particularly interesting nitro compounds as they are found as ligands in protein structures and are used in important medicine. For example, isosorbide dinitrate is commonly prescribed to treat chronic congestive heart failure 15 and chloramphenicol is an inexpensive and abundantly used antibiotic; 16 both are listed as an essential medicine by the world health organization (WHO).…”

Factors Impacting σ- and π-Hole Regions as Revealed by the Electrostatic Potential and Its Source Function Reconstruction: The Case of 4,4′-Bipyridine Derivatives

“…Many XB and ChB donors reported so far are based on the use of electron-attracting heterocyclic systems which induce polarization in bound atoms of Groups VI and VII, enhancing their electrophilic character [ 12 , 23 , 24 ]. Fluorination also increases σ- and π-hole depth [ 25 ], π-holes being electron deficient regions often observed on polarized double bond and π-acidic aromatics, and able to interact with nucleophiles [ 26 , 27 ].…”