Underappreciated Chemical Interactions in Protein-Ligand Complexes

Abstract

Non-covalent interactions lie at the bases of the molecular recognition process. In medicinal chemistry, understanding how bioactive molecules interact with their target can help to explain structure-activity relationships (SAR) and improve potency of lead compounds. In particular, computational analysis of protein-ligand complexes can help to unravel key interactions and guide structure-based drug design.The literature describing protein-ligand complexes is typically focused on few types of non-covalent interactions (e.g., hydrophobic contacts, hydrogen bonds, and salt bridges). Stacking interactions involving aromatic rings are also relatively well known to medicinal chemistry practitioners. Potency optimization efforts are often focused on targeting these interactions. However, a variety of underappreciated interactions were shown to have a relevant effect on the stabilization of protein-ligand complexes. This chapter aims at listing selected non-covalent interactions and discuss some examples on how they can impact drug design.

Keywords: Cation–π; Drug design; Halogen bond; Halogen–π; Hydrophobic interactions; Medicinal chemistry; Non-classical hydrogen bond; Non-covalent interactions; Orthogonal multipolar interactions; Quantum mechanics; π–π stacking.