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【PharmaBlock (Nanjing) 】Application of Halogen Bond in Drug Discovery

  • 2023/10/30
  • サプライヤニュース

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Introduction

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Halogen bond (XB) is a highly directional and specific interaction driven by the σ-hole, a positively charged region on the hind side of X along the R−X bond axis that is caused by an anisotropy of electron density on the halogen (Figure 1a)1. Halogen bond is formed between a covalently bonded halogen atom (XB donor) and a nucleophile (i.e., Lewis base; XB acceptor) (Figure 1b). In general, heavy halogens, such as -Cl, -Br and -I, can form halogen bonds while fluorine cannot2.

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Figure1a)                         Figure1b)

Figure 1: 1a) The anisotropy of the electron density on the Halogen. The positive surface potential (including the σ-hole on the halogen) is colored in red, and the negative surface potential is colored in light blue. 1b) Typical Halogen bonds: one covalently bonded halogen atom and a nucleophile. R-X... acceptor angle is close to 180o.

In protein−ligand environments, halogen bonds can be formed between a halogenated ligand and any accessible Lewis base in the binding pocket, such as the backbone carbonyl oxygen, hydroxyls in serine, threonine, and tyrosine, carboxylate groups in aspartate and glutamate, sulfur in cysteine and methionine, nitrogen in histidine, and the π surface of phenylalanine, tyrosine, histidine, and tryptophan1. One typical example is halogen atoms getting involved in the hinge region binding instead of the canonical hinge binders (Figure 2)1.

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Figure2 a)

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