Hidden Interactions: Quantum Perspectives in Drug Design

Noncovalent intermolecular interactions play a key role in ligand recognition, affinity, and specificity. This chapter provides an overview, with literature examples, of underexplored interactions that contribute to molecular binding, including weak hydrogen bonding; anion-π and cation-π interactions; Bürgi-Dunitz and tetrel interactions; halogen and chalcogen bonding; and S···π, C···π, O···π, N···π, and amide···π interactions. These interactions are often overlooked, and in many of the examples described here, ligands were not initially designed to exploit them-even though reports show that, collectively, they can fine-tune ligand-protein recognition in drug design. IsoStar contour density surfaces are included to visualize the geometric preferences of each interaction. Additionally, where applicable, we include evaluation of the geometry and prevalence of these interactions through database mining and quantification of their energetics using quantum mechanical methods, like density functional theory.