Halogen Bonds in Ligand–Protein Systems: Molecular Orbital Theory for Drug Design

Abstract

Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug–receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the same bonding interactions as hydrogen bonding. Besides the electrostatic and the dispersion interactions, our bonding analyses, based on quantitative Kohn–Sham molecular orbital theory together with energy decomposition analysis, reveal that donor–acceptor interactions and steric repulsion between the occupied orbitals of the halogenated ligand and the protein need to be considered more carefully within the drug design process.

Spodium Bonds in Biological Systems: Expanding the Role of Zn in Protein Structure and Function

“…They are based on electropositive potential regions located on the extension of covalent X–Ae, X–Hal, X–Ch, X–Pn, and X–Tr bonds, which are able to interact in a favorable manner with electron-rich species (i.e., a lone pair, an anion, or a π-system). Their study and recognition by the scientific community have led to powerful and novel applications in the fields of rational drug design, − molecular aggregation, − or even tuning self-assembly phenomena, − among others.…”

Regio and stereochemical probes of iodine interactions in diiodocyclododecanes

“…Many applications related to these properties have been recently reported in a series of halogen‐bond papers, ranging from effects on odor to the design of semiconductor nanowires and beyond [5–12]. However, updated studies have shown that halogen bonding would be a result of orbital interactions, where a base donates electrons to an σ* C–X orbital (X = halogen), whose electron‐accepting coefficient is largely on the same region of the old‐fashioned σ‐hole [13, 14]. A similar origin has been found for the chalcogen bonding, that is, this interaction is dominated by an n → σ* electron delocalization, which is at least as stabilizing as conventional hydrogen bonds and can be useful for conformational control and molecular recognition phenomena [15, 16].…”

The C2N surface as a highly selective sensor for the detection of nitrogen iodide from a mixture of NX3 (X = Cl, Br, I) explosives

“…Halogen bonding is an intermolecular force of attraction in which halogen atoms accept electrons from highly electronegative atoms. 72 Halogen bonding interactions have been the topic of recent interest in the scientic community because of their potential for use in supramolecular chemistry, 73,74 crystal engineering, 75,76 molecular recognition, 77 rational drug design, 78 and catalysis. 79 In these interactions, a part of the halogen acts as the electrophile (s-hole).…”