Increasing Binding Constants of Ligands to Carbonic Anhydrase by Using “Greasy Tails”

Jinming Gao, Shuang Qiao, George M. Whitesides

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82 Scopus citations

Abstract

Two series of para-substituted benzenesulfonamides have been examined as inhibitors for bovine carbonic anhydrase II (CAII, EC 4.2.1.1). Both series have hydrophobic alkyl group R connected by amide linkages to the aromatic ring (H2NO2SC6H4-CH2NHCOR1 and H2NO2SC6H4-CONR2R3). The free energy of partitioning (ΔGp) of these ligands between water and octanol had similar, linear correlations with the molecular surface areas of the hydrophobic groups R; ΔGp was only relatively weakly influenced by the linkage to the benzenesulfonamide and the detailed structure of the group R. Binding of these ligands to CAII was more complicated. For compounds having the structure H2NO2SC6H4-L-R, the dependence of the free energy of binding to CAII on the surface area of the hydrocarbon (fluorocarbon) group R for different -L-R was (dΔGb/dA, kcal/(mo·100 Å2)): -CH2NHCORH, -0.71 ± 0.03; -CH2NHCORF, -0.72 ± 0.07; -CONHCH2RH, —2.5 ± 0.1; and -CONHCH2RF, —2.7 ± 0.3. The available data permit several conclusions: (i) details (linear, branched, cyclic) of the structure of the group Rh are relatively unimportant in determining binding constants (although cyclic structures may bind slightly more strongly than acyclic ligands with the same carbon number); (ii) for a given class of compounds, binding constants of hydrocarbons and fluorocarbons having the same surface area are very similar; and (iii) the nature of the linker L influences the sensitivity of binding to the surface area of the group R, presumably by its influences in positioning the group in the binding pocket of the enzyme. Fluorocarbons seem to be more hydrophobic than hydrocarbons of the same carbon number because they have larger areas of hydrophobic surface; the hydrophobicity of hydrocarbon and fluorocarbon surfaces are similar, after correction for differences in area.

Original languageEnglish (US)
Pages (from-to)2292-2301
Number of pages10
JournalJournal of Medicinal Chemistry
Volume38
Issue number13
DOIs
StatePublished - Jun 1 1995

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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