title: Halogen bonding for rational drug design and new drug discovery.
abstract: BACKGROUND
  A large number of drugs and drug candidates in clinical development contain halogen substituents. For a long time, only the steric and lipophilic contributions of halogens were considered when trying to exploit their effects on ligand binding. However, the ability of halogens to form stabilizing interactions, such as halogen bonding, hydrogen bonding and multipolar interactions, in biomolecular systems was revealed recently. Halogen bonding, the non-covalent interaction in which covalently bound halogens interact with Lewis bases, has now been utilized in the context of rational drug design.
  
  
  METHODS
  The purpose of this review is to show how halogen bonding could be used in drug design, and in particular, to stimulate researchers to apply halogen bonding in lead optimization. This review article covers the recent advances relevant to halogen bonding in drug discovery and biological design over the past decade, including database survey of this interaction in protein-ligand complexes, molecular mechanical investigations of halogen bonding in drug discovery and applications of this interaction in the development of halogenated ligands as inhibitors and drugs for protein kinases, serine protease factor Xa, HIV reverse transcriptase and so on.
  
  
  CONCLUSIONS
  Halogen bonding should intentionally be used as a powerful tool, comparable with hydrogen bonding, to enhance the binding affinity and also influence the binding selectivity. Rational design of new and potent inhibitors against therapeutic targets through halogen bonding continues to be an exciting area, which will be further elucidated with the combination of various experimental techniques and theoretical calculations in the forthcoming years.
authors.affiliation: Key Laboratory for Advanced Materials and Department of Chemistry, East China University of Science and Technology, Shanghai, China. yxlu@ecust.edu.cn
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Lu
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xu
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.forename: Honglai
authors.initials: H
authors.lastname: Liu
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D006219:Halogens; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011956:Receptors, Cell Surface; D000077022:Survivin; D054303:HIV Reverse Transcriptase