Do Halogen–Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand–Protein Binding?

Abstract

Halogens are present in a significant number of drugs, contributing favorably to ligand–protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand–protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C–X···HBD orientations. Notably, the orientation dependence of the halogen–HBD (X–HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from −2 to −14 kcal/mol. This contrasts halogen bonds in that X–HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand–protein binding and, therefore, should be actively considered during rational ligand design.

Molecular Bases for Anesthetic Agents: Halothane as a Halogen‐ and Hydrogen‐Bond Donor

“…The small Nc values obtained for the Br⋅⋅⋅O and Cl⋅⋅⋅O interactions in the halothane/HMPA co‐crystal suggest that the HaBs observed in the protein adducts mentioned above are not induced by the binding, but play an active role in inducing, or driving, the binding. This is consistent with the emerging evidences on the general relevance of specific interactions involving halogen atoms in securing ligand–protein binding . Finally, the proven ability of hydrogen, bromine, and chlorine atoms of halothane to act as electrophilic sites, and therefore the possibility for the agent to form two or three interactions, gives an atomic rationale for the different pharmacological activity and catabolism of its enantiomers…”

Halogen bonding with the halogenabenzene bird structure, halobenzene, and halocyclopentadiene

“…This was also observed for halogenated uracil• • •H 2 O . Thus, whereas halogen‐hydrogen‐bond donor interactions may be more favorable than halogen bonding interactions for the lighter halogens, as suggested by Lin and MacKerell, this may not necessarily be the case for the heavier halogens.…”

“…Presumably this minimum disappears when allowing for geometry relaxation. The interaction energies of the double-hydrogen-bonded complexes are −12.5, −12.5, −12.1 and −11.6 kJ/mol for X Cl, Br, I and [22,23] Thus, whereas halogen-hydrogen-bond donor interactions may be more favorable than halogen bonding interactions for the lighter halogens, as suggested by Lin and MacKerell, [55] this may not necessarily be the case for the heavier halogens.…”

“…[19] Another study concluded that M06-2X performs better than B3LYP for halogen-bonding interactions, but did not consider double hybrids. [54] Lin and MacKerell [55] studied complexes of halobenzenes and halogenated ethane molecules (with halogens ranging from fluorine to bromine) with model compounds serving as H-bond donors and H-bond acceptors in both perpendicular (C-X• • •Y = 90 ) and linear (C-X• • •Y = 180 ) orientations (X halogen; Y O or N in model compound). They concluded that halogens acting as H-bond acceptors may make a more favorable contribution to ligand binding than X-bonds.…”

Identification of an Overlooked Halogen‐Bond Synthon and Its Application in Designing Fluorescent Materials

“…[3,12,18,19] However, oxygen was studied to al esser extent.I nb iological systems, CÀX···O( X= F, Cl, Br,I )i sa ctually one of the important interactions in protein-ligand complexes, in whichi ti se ven more widely encountered than CÀX···N. [20,21] Compared with the sp 3 oxygen atom in ethers, the sp 2 oxygen atom in carbonyl compounds exhibits less steric hindrance and increased electron density in the p bond. This means that sp 2 oxygen has ag reater probability of forming halogen bonds.…”