Enzymatic transition state theory and transition state analogue design

Kinetic isotope effects linked to computational chemistry provide sufficient information to develop geometric and electrostatic potential maps of enzymatic transition states. These are blueprints for the design of transition state analogues. Chemically stable molecules that resemble the transition states provide a wealth of inhibitors with dissociation constants in the picomolar to femtomolar range. Several of these have entered clinical trials, and others are in preclinical development. Determination of KIEs coupled to computational and synthetic chemistry can contribute significantly to the development of a broad spectrum of useful enzymatic inhibitors.