Jm. Gao et al., INCREASING BINDING CONSTANTS OF LIGANDS TO CARBONIC-ANHYDRASE BY USING GREASY TAILS, Journal of medicinal chemistry, 38(13), 1995, pp. 2292-2301
Two series of para-substituted benzenesulfonamides have been examined
as inhibitors for bovine carbonic anhydrase II (CAII, EC 4.2.1.1). Bot
h series have hydrophobic alkyl group R connected by amide linkages to
the aromatic ring (H2NO2SC6H4-CH(2)NHCOR(1) and H2NO2SC6H4-CONR(2)R(3
)). The free energy of partitioning (Delta Gp) Of these ligands betwee
n water and octanol had similar, linear correlations with the molecula
r surface areas of the hydrophobic groups R; Delta Gp was only relativ
ely weakly influenced by the Linkage to the benzenesulfonamide and the
detailed structure of the group R. Binding of these ligands to CAII w
as 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
(d Delta G(b)/dA, kcal/(mol . 100 Angstrom(2))): -CH(2)NHCOR(H), -0.71
+/- 0.03; -CH(2)NHCOR(F), -0.72 +/- 0.07; -CONHCH(2)R(H), -2.5 +/- 0.
1; and -CONHCH(2)R(F), -2.7 +/- 0.3. The available data permit several
conclusions: (i) details (linear, branched, cyclic) of the structure
of the group R(H) are relatively unimportant in determining binding co
nstants (although cyclic structures may bind slightly more strongly th
an acyclic ligands with the same carbon number); (ii) for a given clas
s of compounds, binding constants of hydrocarbons and fluorocarbons ha
ving the same surface area are very similar; and (iii) the nature of t
he 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 hyd
rophobic than hydrocarbons of the same carbon number because they have
larger areas of hydrophobic surface; the hydrophobicity of hydrocarbo
n and fluorocarbon surfaces are similar, after correction for differen
ces in area.