Halogen bonds as orthogonal molecular interactions to hydrogen bonds

Abstract

Halogen bonds (X-bonds) are shown to be geometrically perpendicular to and energetically independent of hydrogen bonds (H-bonds) that share a common carbonyl oxygen acceptor. This orthogonal relationship is accommodated by the in-plane and out-of-plane electronegative potentials of the oxygen, which are differentially populated by H- and X-bonds. Furthermore, the local conformation of a peptide helps to define the geometry of the H-bond and thus the oxygen surface that is accessible for X-bonding. These electrostatic and steric forces conspire to impose a strong preference for the orthogonal geometry of X- and H-bonds. Thus, the optimum geometry of an X-bond can be predicted from the pattern of H-bonds in a folded protein, enabling X-bonds to be introduced to improve ligand affinities without disrupting these structurally important interactions. This concept of orthogonal molecular interactions can be exploited for the rational design of halogenated ligands as inhibitors and drugs, and in biomolecular engineering.

Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor

“…Interestingly, the 7-bromo analogue (12e) demonstrates a significantly greater functional affinity compared to the corresponding 7-trifluoromethyl (12f) and 7-chloro (12d) analogues, yet these substituents have comparable vdW radii. This may result from the greater degree of halogen bonding 36,37 exhibited by bromine by virtue of its larger positive electrostatic potential compared to chlorine. The ensuing sigma hole has a greater potential to interact with electronegative atoms (such as hydroxyls in Ser, Thr and Tyr) within the orthosteric binding pocket via halogen bonding interactions.…”

Bicomponent Supramolecular Architectures at the Vacuum–Solid Interface

“…Similar to H-bonding, X-bonding can also direct assembly efficiently. 104,105,106 For a general review on X-bonding in supramolecular chemistry, see Beer et al 107 and Cavallo et al 108,109 The X-bond is an alternative to the H-bond and presents similar properties, especially in terms of directional bonding. It has already been exploited to form porous networks on …”

3D-QSAR studies of triazolopyrimidine derivatives of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics, docking, and genetic algorithm-based methods

“…In recent years, the role of halogens especially fluorine in medicinal chemistry and drug design has been studied extensively [33][34][35][36], as fluorine show quite distinct qualities than other halogens due to its high electronegativity and low polarisability. According to the SAR fundamental theory, similar structures should have similar activities, but in the present dataset, compounds 10 and 14, two highly potent inhibitors, are somewhat dissimilar as also shown by their presence in two distinct clusters (Fig.…”