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 1010-1015, and Michaelis complexes often have dissociation constants in the range of 10−3-10−6 M, it is proposed that transition state complexes are bound with dissociation constants in the range of 10−14 -10−23 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.