Conformational aspects of inhibitor design: enzyme-substrate interactions in the transition state.
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.
Wolfenden
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Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599, USA.
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D011487:Protein Conformation
D004791:Enzyme Inhibitors