Increasing binding constants of ligands to carbonic anhydrase by using "greasy tails"

Jinming Gao, Shuang Qiao, George M. Whitesides

Research output: Contribution to journalArticle

80 Citations (Scopus)

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-CH2NHCOR 1 and H2NO2SC6H4-CONR2R 3). 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/(mol·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 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
StatePublished - 1995

Fingerprint

Fluorocarbons
Carbonic Anhydrases
Hydrocarbons
Ligands
Carbon
Carbonic Anhydrase II
Octanols
Free energy
Hydrophobic and Hydrophilic Interactions
Amides
Hydrophobicity
Water
Enzymes
benzenesulfonamide

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Increasing binding constants of ligands to carbonic anhydrase by using "greasy tails". / Gao, Jinming; Qiao, Shuang; Whitesides, George M.

In: Journal of Medicinal Chemistry, Vol. 38, No. 13, 1995, p. 2292-2301.

Research output: Contribution to journalArticle

Gao, Jinming ; Qiao, Shuang ; Whitesides, George M. / Increasing binding constants of ligands to carbonic anhydrase by using "greasy tails". In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 13. pp. 2292-2301.
@article{6fd556ca30dc411e8ab17a10a7ed5940,
title = "Increasing binding constants of ligands to carbonic anhydrase by using {"}greasy tails{"}",
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-CH2NHCOR 1 and H2NO2SC6H4-CONR2R 3). 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/(mol·100 {\AA}2)): -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 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.",
author = "Jinming Gao and Shuang Qiao and Whitesides, {George M.}",
year = "1995",
language = "English (US)",
volume = "38",
pages = "2292--2301",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "13",

}

TY - JOUR

T1 - Increasing binding constants of ligands to carbonic anhydrase by using "greasy tails"

AU - Gao, Jinming

AU - Qiao, Shuang

AU - Whitesides, George M.

PY - 1995

Y1 - 1995

N2 - 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-CH2NHCOR 1 and H2NO2SC6H4-CONR2R 3). 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/(mol·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 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.

AB - 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-CH2NHCOR 1 and H2NO2SC6H4-CONR2R 3). 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/(mol·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 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.

UR - http://www.scopus.com/inward/record.url?scp=0028998264&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028998264&partnerID=8YFLogxK

M3 - Article

VL - 38

SP - 2292

EP - 2301

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 13

ER -