The strength of weak interactions: aromatic fluorine in drug design.
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-pi...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.
Dimagno
Stephen G
SG
Department of Chemistry & Center for Materials Research & Analysis, University of Nebraska - Lincoln, Lincoln, NE 68588-0304, USA. sdimagno1@unl.edu
Sun
Haoran
H
D000818:Animals; D015195:Drug Design; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry* / Q000494:pharmacology; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D017611:Fluorine Compounds; D006845:Hydrocarbons, Fluorinated; D005461:Fluorine