, , , ,

By Andy Coop

Halogens (such as fluorine, chlorine, bromine) are a key component of many natural products, especially marine natural products, but have been widely utilized in the design of drugs. The reason is the unique properties of halogens, such as fluorine replacing hydrogen on aromatics rings, as they share a similar size, yet the halogen will prevent metabolism (through hydroxylation) of the aromatic ring. Also,  the addition of halogens increases lipophilicity, thus transport across lipid membranes, and their electronic properties alters the electronic properties of the drug molecule. All these properties are widely utilized in drug optimization, and the utilization of halogens to mimic functional groups able to participate in hydrogen bonds with the biological target seems an obvious extension but, surprisingly, is more complicated than first appears.

Through the pioneering work of P. Shing Ho, it has become clear that halogens interact with hydrogen bond acceptors on biological targets. Although halogens are electron rich, a positive “sigma-hole” exists on the face of the halogen, directly linear to the bond to the carbon. Thus, drug design has tended to focus on utilizing this property of halogens interacting with electron rich atoms (such as oxygen) in optimizing drug-target interactions. However, to a new investigator not familiar with the literature, halogens acting at hydrogen bond acceptors appear surprising, and there are numerous examples where a halogen was introduced into a molecule to act as a hydrogen-bond acceptor. Indeed, my research group even used this approach and reasoning in the design of metabolically stable analogs of g-hydroxybutyrate several years ago, the same year as the halogen bond was described by Ho.

A recent study by my colleagues in the MacKerell group focused on this apparent dichotomy, and showed through computational means that halogens should indeed participate in both hydrogen bond accepting and donating interactions. The key feature is the directionality of the interactions with the sigma-hole being linear to the carbon-halogen bond, and the hydrogen-bond accepting properties being perpendicular. MacKerell presents many examples from the literature (such as X-ray crystal structures) that clearly show the orthogonal directionality, thereby adding additional evidence for this direction-dependent bifuctional property of halogens.

The fact that the two differing interactions are orthogonal, coupled with the ability to specify length (chlorine vs. bromine), opens up new ways to utilize the humble halogen in rational drug design to specifically introduce the optimal substituents for enhanced affinity at, and selectivity for, the desired target.

Andrew Coop, Ph.D., is an AAPS Fellow and professor and associate dean for Academic Affairs at the University of Maryland School of Pharmacy.