Using halogen bonds to address the protein backbone: a systematic evaluation

Abstract

Halogen bonds are specific embodiments of the sigma hole bonding paradigm. They represent directional interactions between the halogens chlorine, bromine, or iodine and an electron donor as binding partner. Using quantum chemical calculations at the MP2 level, we systematically explore how they can be used in molecular design to address the omnipresent carbonyls of the protein backbone. We characterize energetics and directionality and elucidate their spatial variability in sub-optimal geometries that are expected to occur in protein-ligand complexes featuring a multitude of concomitant interactions. By deriving simple rules, we aid medicinal chemists and chemical biologists in easily exploiting them for scaffold decoration and design. Our work shows that carbonyl-halogen bonds may be used to expand the patentable medicinal chemistry space, redefining halogens as key features. Furthermore, this data will be useful for implementing halogen bonds into pharmacophore models or scoring functions making the QM information available for automatic molecular recognition in virtual high throughput screening.

Insights into halogen bond-driven enantioseparations

“…2B). The carbonyl-halogen bonds have been widely studied in medicinal chemistry, which showed to have a relevant role in protein-pharmacophore complexes [24,25]. In nature, halogenated XB donors are not unusual and the selective binding of the hormone thyroxine (T4) to its transporter protein transthyretin involves iodine-carbonyl oxygen interaction, for instance [26].…”

Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition

“…Even though the IÁÁÁO distance in IA6 is appreciably greater than the crystallographic distance, it is still less than the sum of the van der Waals radii (Table 1). It should be pointed out here that optimal binding geometries are not generally observed in ligand-protein binding due to the interplay of competing interactions [7,36]. Interestingly, the most populated MD values for the XÁÁÁO=C angle are smaller, and therefore closer to the (in theory) ideal value of 1208, than those found in the crystal structures.…”

“…Indeed, a theoretical study of the interactions between chloro-, bromo-and iodobenzene as halogen bond donors, and N-methylacetamide as the acceptor, gave values of 171.2°, 177.4°and 175.2°for the R-XÁÁÁO angle, and 106.7°, 116.7°and 119.4°for the XÁÁÁO=C angle, respectively. The same publication calculated the XÁÁÁO internuclear distances as 95.4, 90.2 and 87.4 % of the sum of the van der Waals radii of these halogens and oxygen [7]. Many theoretical and experimental studies have been done on halogen bonding, initially because of its possible applications in crystal engineering and in the development of solid electronic materials and polymers [8,9].…”

“…Halogen bonds have also been observed fairly recently in biological systems [10], and they are beginning to be considered in rational drug design [11][12][13][14]. Nevertheless, this aspect can still be considered to be in its infancy despite the high likelihood of such interactions occurring in environments such as the carbonyl-rich protein active sites [7].…”

In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors

“…These compounds were employed in this work. contact interactions seen in drugs bearing the group PheX, (F, Cl, Br, and I) where X acts as a Lewis acid allowing the interaction with the carbonyl within residues, which acts as a Lewis base [12]. Halogen bonding is explained on the basis of "s-hole" caused by the uneven electronic distribution of the PheX functionality, forming a positively charged region that interacts with a nucleophile such as carbonyl observed in protein backbones [13].…”