Addressing Methionine in Molecular Design through Directed Sulfur–Halogen Bonds

Halogen bonds are directional interactions involving an electron donor as binding partner. Employing quantum chemical calculations, we explore how they can be used in molecular design to address the sulfur atom in a methionine residue in a previously neglected, directed manner. We characterize energetics and directionality of these halogen bonds and elucidate their spatial variability in suboptimal geometries that are expected to occur in protein–ligand complexes featuring a multitude of concomitant interactions. We derive simple rules allowing medicinal chemists and chemical biologists to easily determine preferred areas of interaction within a binding site and to exploit them for scaffold decoration and design. Our work shows that sulfur–halogen bonds may be used to expand the patentable medicinal chemistry space. We demonstrate their potential to increase binding affinities and suggest that they can significantly contribute to inducing and tuning subtype selectivities.