Incorporating halogens within a drug’s structure is often an important consideration, with an emphasis on maximizing favorable halogen interactions with the protein binding site. In recent years, significant attention has been placed on the halogen bonding (XB) interaction, where a Lewis-basic atom interacts with an electron poor region of the halogen (known as a σ-hole). However, as medicinal chemists have begun to look more holistically at the environments that tend to surround halogenated drug fragments, it is apparent that these surroundings are often highly hydrophobic and that halogens have substantial contact with other (non-basic) hydrophobic partners. An expanded view of the complicated interactions halogens have with their hydrophobic partners continues to be important in order to best use them to fill hydrophobic pockets. We are interested in experimentally characterizing halogen behavior within carbon-rich clefts, similar to aromatic amino acid pockets, using molecular balances (Figure 1). These model systems can effectively isolate and quantify weak halogen interactions in the solution phase, as well as provide valuable crystallographic insights. Our focus is on alkyl F and Cl fragments, which are increasingly applied in drug design, and will be highlighted in the presentation.

Halogens in hydrophobic pockets: Evaluating cooperativity in small spaces

ACS Spring 2022

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