Kinetic aspects of structure-activity relations: the binding of sulphonamides by carbonic anhydrase.

Abstract

The fast kinetics of binding of sulphonamides to carbonic anhydrase have been examined. Six homologous series of sulphonamides have been studied. In all cases the increase in binding constant in a homologous series is due mainly to an increase in the association rate constant. Meta- and ortho-substituted sulphonamides have lower binding constants also mainly due to a lower association rate constant. The binding of sulphonamides to apocarbonic anhydrase has been measured by a specific affinity method. The effects of homologous series are largely reproduced on the apoenzyme but the effects of positional isomerization are not; the binding process is pH-insensitive. Evidence is presented that the binding process for sulphonamides and carbonic anhydrase involves an intermediate non-coordinate complex which is then converted into the final coordinate complex. Structure-activity relations in the binding of sulphonamides to carbonic anhydrase are examined on the basis of effects on ( a ) the stability of the intermediate complex; ( b ) the rate of isomerization into the coordinate complex; ( c ) the dissociation rate constant.