Conformational aspects of inhibitor design: enzyme–substrate interactions in the transition state Review Article

The theory of absolute reaction rates suggests that enzymes, like other catalysts, can enhance the rate of a reaction only to the extent that they bind the altered substrate in the transition state (S‡) more tightly than they bind the substrate in the ground state (S). ES dissociation constants commonly fall in the physiological range, but recent kinetic studies indicate that formal ES‡ dissociation constants of less than 10−20 M are achieved by enzymes of several classes. Studies with stable analogues suggest that these remarkable powers of discrimination involve a tendency of the enzyme to close around S‡ in such a way as to maximize binding contacts; that several parts of the substrate contribute to S‡ binding; and that their contributions to binding affinity can be strongly synergistic.