Abstract

Non-covalent interactions like hydrogen bonding, hydrophobic interactions and salt bridges, have been our primary focus in designing and optimizing drugs. Recently, there is mounting evidence that non-covalent interactions involving aromatic rings are also potent forces for the recognition between small drug-like compounds and their targets. Understanding of these interactions and their physical origin is of significant interest for improving the current drug design strategy. Hence, numerous efforts have been devoted to elucidating the structural, geometrical, energetic, and thermodynamic properties of these interactions, which include π-π, cation-π and anion-πinteractions. In this review, we established a framework to systematically understand the structural basis and physicochemical properties of the aromatic interactions at the binding interface of protein-ligand complexes. Firstly, we presented an introduction including the definition, universality, energy components, geometry conformations and substituent effects of these interactions. Secondly, we retrospected the widely employed computational approaches for studying these interactions, including quantum mechanical calculations and crystallographic data mining. Finally, we illustrated with several representative protein-ligand systems to show how the aromatic interactions contribute to the design and optimization of ligand in both affinity and specificity.

Keywords: π-π interactions, cation-π, anion-π interactions, quantum mechanical calculations, crystallographic data mining, rational drug design, Acetylcholine esterase (AChE), HMG-CoA reductase (HMGR), serine protease factor Xa (fXa).