The strength of weak interactions: Aromatic fluorine in drug design

Stephen G. DiMagno, Haoran Sun

Research output: Contribution to journalReview article

52 Citations (Scopus)

Abstract

Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-π X and C-F X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.

Original languageEnglish (US)
Pages (from-to)1473-1482
Number of pages10
JournalCurrent Topics in Medicinal Chemistry
Volume6
Issue number14
DOIs
StatePublished - Jul 1 2006

Fingerprint

Fluorination
Fluorine
Halogenation
Drug Design
Hydrocarbons
Pharmaceutical Preparations
Fluorocarbons
Molecular interactions
Substitution reactions
Molecules
Geometry
Proteins

Keywords

  • Arene-arenen interactions
  • C-C framework
  • Carbonic anhydrase inhibitors
  • Fluorination
  • Fluorobenzenes
  • Intermolecular interaction

ASJC Scopus subject areas

  • Drug Discovery

Cite this

The strength of weak interactions : Aromatic fluorine in drug design. / DiMagno, Stephen G.; Sun, Haoran.

In: Current Topics in Medicinal Chemistry, Vol. 6, No. 14, 01.07.2006, p. 1473-1482.

Research output: Contribution to journalReview article

DiMagno, Stephen G. ; Sun, Haoran. / The strength of weak interactions : Aromatic fluorine in drug design. In: Current Topics in Medicinal Chemistry. 2006 ; Vol. 6, No. 14. pp. 1473-1482.
@article{bb08972d24e645f291a89ade9a36bdc8,
title = "The strength of weak interactions: Aromatic fluorine in drug design",
abstract = "Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-π X and C-F X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.",
keywords = "Arene-arenen interactions, C-C framework, Carbonic anhydrase inhibitors, Fluorination, Fluorobenzenes, Intermolecular interaction",
author = "DiMagno, {Stephen G.} and Haoran Sun",
year = "2006",
month = "7",
day = "1",
doi = "10.2174/156802606777951127",
language = "English (US)",
volume = "6",
pages = "1473--1482",
journal = "Current Topics in Medicinal Chemistry",
issn = "1568-0266",
publisher = "Bentham Science Publishers B.V.",
number = "14",

}

TY - JOUR

T1 - The strength of weak interactions

T2 - Aromatic fluorine in drug design

AU - DiMagno, Stephen G.

AU - Sun, Haoran

PY - 2006/7/1

Y1 - 2006/7/1

N2 - Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-π X and C-F X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.

AB - Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-π X and C-F X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.

KW - Arene-arenen interactions

KW - C-C framework

KW - Carbonic anhydrase inhibitors

KW - Fluorination

KW - Fluorobenzenes

KW - Intermolecular interaction

UR - http://www.scopus.com/inward/record.url?scp=33746610484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746610484&partnerID=8YFLogxK

U2 - 10.2174/156802606777951127

DO - 10.2174/156802606777951127

M3 - Review article

C2 - 16918463

AN - SCOPUS:33746610484

VL - 6

SP - 1473

EP - 1482

JO - Current Topics in Medicinal Chemistry

JF - Current Topics in Medicinal Chemistry

SN - 1568-0266

IS - 14

ER -