Halogenation is an important approach in lead optimization for drug development and about half of the molecules used in high-throughput screening are halogenated. However, there is neither a suitable theoretical algorithm for evaluating the interaction between the halogen atoms of a ligand and its target protein nor a detailed understanding of how a halogen atom interacts with electron-rich atoms or groups of the residues in the binding pocket. In this Perspective, we concentrate on nonbonding interactions of halogens from both crystallographic data and theoretical viewpoints. It is found that organic halogen atoms are favorably involved in a wide variety of noncovalent protein-ligand interactions, such as halogen bonds C-X...O and hydrogen bonds C-X...H, that show remarkable differences in terms of the geometrical and energetic features. In biological molecules, heavier halogens prefer to form linear interactions with oxygen atoms and aromatic pi systems as compared to N or S, while the mean intermolecular distances for these types of halogen bonds increase with the radius or polarizability of halogen atoms, viz., Cl < Br < I. Furthermore, F...H interactions in protein-ligand complexes exhibit disparate behavior relative to X...H (X = Cl, Br, I) counterparts. These observed tendencies of the interactions involving halogens are subsequently rationalized by means of ab initio calculations using small model systems. The results presented herein should be of great use in the rational design of halogenated ligands as inhibitors and drugs as well as in biological engineering.

Halogen bonding, a specific intermolecular noncovalent interaction, plays crucial roles in fields as diverse as molecular recognition, crystal engineering, and biological systems. This paper presents an ab initio investigation of a series of dimeric complexes formed between bromobenzene and several electron donors. Such small model systems are selected to mimic halogen bonding interactions found within crystal structures as well as within biological molecules. In all cases, the intermolecular distances are shown to be equal to or below sums of van der Waals radii of the atoms involved. Halogen bonding energies, calculated at the MP2/aug-cc-pVDZ level, span over a wide range, from -1.52 to -15.53 kcal/mol. The interactions become comparable to, or even prevail over, classical hydrogen bonding. For charge-assisted halogen bonds, calculations have shown that the strength decreases in the order OH- > F- > HCO2- > Cl- > Br-, while for neutral systems, their relative strengths attenuate in the order H2CS > H2CO > NH3 > H2S > H2O. These results agree with those of the quantum theory of atoms in molecules (QTAIM) since bond critical points (BCPs) are identified for these halogen bonds. The QTAIM analysis also suggests that strong halogen bonds are more covalent in nature, while weak ones are mostly electrostatic interactions. The electron densities at the BCPs are recommended as a good measure of the halogen bond strength. Finally, natural bond orbital (NBO) analysis has been applied to gain more insights into the origin of halogen bonding interactions.

For proof-of-concept of halogen bonding in drug design, a series of halogenated compounds were designed based on a lead structure as new inhibitors of phosphodiesterase type 5. Bioassay results revealed a good correlation between the measured bioactivity and the calculated halogen bond energy. Our X-ray crystal structures verified the existence of the predicted halogen bonds, demonstrating that the halogen bond is an applicable tool in drug design and should be routinely considered in lead optimization.

A systematic study of halogen bonding interactions in gas phase and in solution was carried out by means of quantum chemical DFT/B3LYP method. Three solvents with different polarities (chloroform, acetone, and water) were selected, and solvation effects were considered using the polarized continuum model (PCM). For charged halogen-bonded complexes, the strength of the interactions tends to significantly weaken in solution, with a concomitant elongation of intermolecular distances. For neutral systems, halogen bond distances are shown to shorten and the interaction energies change slightly. Computations also reveal that in the gas phase the binding affinities decrease in the order Cl(-) > Br(-) > I(-), while in solution the energy gaps of binding appear limited for the three halide anions. According to free energy results, many systems under investigation are stable in solution. Particularly, calculated free energies of formation of the complexes correlate well with halogen-bonding association constants determined experimentally. The differences of the effects of solvent upon halogen and hydrogen bonding were also elucidated. This study can establish fundamental characteristics of halogen bonding in media, which would be very helpful for applying this noncovalent interaction in medicinal chemistry and material design.

The hydrogen bond acceptor capability of halogens has long been underappreciated in the field of biology. In this work, we have surveyed structures of protein complexes with halogenated ligands to characterize geometrical preferences of C-X...H contacts and contributions of such interactions to protein-ligand binding affinity. Notably, F...H interactions in biomolecules exhibit a remarkably different behavior as compared to three other kinds of X...H (X = Cl, Br, I) interactions, which has been rationalized by means of ab initio calculations using simple model systems. The C-X...H contacts in biological systems are characterized as weak hydrogen bonding interactions. Furthermore, the electrophile "head on" and nucleophile "side on" interactions of halogens have been extensively investigated through the examination of interactions in protein structures and a two-layer ONIOM-based QM/MM method. In biomolecular systems, C-X...H contacts are recognized as secondary interaction contributions to C-X...O halogen bonds that play important roles in conferring specificity and affinity for halogenated ligands. The results presented here are within the context of their potential applications in drug design, including relevance to the development of accurate force fields for halogens.

A systematic theoretical investigation on a series of dimeric complexes formed between some halocarbon molecules and electron donors has been carried out by employing both ab initio and density functional methods. Full geometry optimizations are performed at the Moller-Plesset second-order perturbation (MP2) level of theory with the Dunning's correlation-consistent basis set, aug-cc-pVDZ. Binding energies are extrapolated to the complete basis set (CBS) limit by means of two most commonly used extrapolation methods and the aug-cc-pVXZ (X = D, T, Q) basis sets series. The coupled cluster with single, double, and noniterative triple excitations [CCSD(T)] correction term, determined as a difference between CCSD(T) and MP2 binding energies, is estimated with the aug-cc-pVDZ basis set. In general, the inclusion of higher-order electron correlation effects leads to a repulsive correction with respect to those predicted at the MP2 level. The calculations described herein have shown that the CCSD(T) CBS limits yield binding energies with a range of -0.89 to -4.38 kcal/mol for the halogen-bonded complexes under study. The performance of several density functional theory (DFT) methods has been evaluated comparing the results with those obtained from MP2 and CCSD(T). It is shown that PBEKCIS, B97-1, and MPWLYP functionals provide accuracies close to the computationally very expensive ab initio methods.

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According to our survey of the Cambridge Structural Database (CSD), a great number of crystal structures, in which halogen bonds and aromatic stacking interactions are present and play an important role in crystal packing, have been extracted. In this work, ab initio calculations at the MP2 level of theory were performed to investigate the mutual influence between halogen bonds and π-π stacking interactions. Different energetic effects are observed in the studied complexes where the two kinds of noncovalent interactions coexist, which can be rationalized by the direction of charge transfer for the two interactions. These effects have been analyzed in detail in terms of the structural, energetic, and charge transfer properties of the complexes. In addition, the quantum theory of atoms in molecules (QTAIM) was also employed to characterize the interactions and to examine the strengthening or weakening of the interactions, depending on the variations of electron density on the bond and cage critical points. Finally, certain crystal structures retrieved from the CSD have been selected to provide experimental evidence of the combination of the two interactions.