title: Non-covalent interactions with aromatic rings: current understanding and implications for rational drug design.
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.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. lutao@cpu.edu.cn.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Qiancheng
authors.initials: Q
authors.lastname: Shen
authors.forename: Xian
authors.initials: X
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D015195:Drug Design; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry
chemical_list: D006841:Hydrocarbons, Aromatic; D004364:Pharmaceutical Preparations; D011506:Proteins