Enzymes catalyze chemical reactions at rates that are astounding relative to uncatalyzed chemistry at the same reaction conditions.  Each catalytic event requires a minimum of three or often more steps, all of which occur within the few milliseconds that characterize typical enzymatic reactions.  According to transition state theory, the smallest fraction of the catalytic cycle is spent in the most important step, that of the transition state.  The original proposals of absolute reaction rate theory for chemical reactions defined the transition state as a distinct species in the reaction coordinate that determined the absolute reaction rate.  Soon thereafter, Linus Pauling proposed that the powerful catalytic action of enzymes could be explained by specific tight binding to the transition state species   Because reaction rate is proportional to the fraction of the reactant in the transition state complex, the enzyme was proposed to increase the concentration of the reactive species.
This proposal was formalized by Wolfenden and coworkers at University of North Carolina at Chapel Hill, who hypothesized that the rate increase imposed by enzymes is proportional to the affinity of the enzyme for the transition state structure relative to the Michaelis complex.  Because enzymes typically increase the non-catalyzed reaction rate by factors of 10-10, and Michaelis complexes often have dissociation constants in the range of 10-10 M, it is proposed that transition state complexes are bound with dissociation constants in the range of 10-10 M.  As substrate progresses from the Michaelis complex to product, chemistry occurs by enzyme-induced changes in electron distribution in the substrate. Enzymes alter the electronic structure by protonation, proton abstraction, electron transfer, geometric distortion, hydrophobic partitioning, and interaction with Lewis acids and bases.  Analogs that resemble the transition state structures should therefore provide the most powerful noncovalent inhibitors known.
All chemical transformations pass through an unstable structure called the transition state, which is poised between the chemical structures of the substrates and products.  The transition states for chemical reactions are proposed to have lifetimes near 10 seconds, on the order of the time of a single bond vibration.  No physical or spectroscopic method is available to directly observe the structure of the transition state for enzymatic reactions, yet transition state structure is central to understanding enzyme catalysis since enzymes work by lowering the activation energy of a chemical transformation.
It is now accepted that enzymes function to stabilize transition states lying between reactants and products, and that they would therefore be expected to bind strongly any inhibitor that closely resembles such a transition state.  Substrates and products often participate in several enzyme catalyzed reactions, whereas the transition state tends to be characteristic of one particular enzyme, so that such an inhibitor tends to be specific for that particular enzyme.  The identification of numerous transition state inhibitors supports the transition state stabilization hypothesis for enzymatic catalysis.
Currently there is a large number of enzymes known to interact with transition state analogs, most of which have been designed with the intention of inhibiting the target enzyme.  Examples include HIV-1 protease, racemases, β-lactamases, metalloproteinases, cyclooxygenases and many others.