Enzyme-Reaction Intermediate Analogues as Examples of Tight Binding Inhibitors

7 ENZYME-REACTION INTERMEDIATE ANALOGUES AS EXAMPLES OF TIGHT BINDING INHIBITORS 

Today a good understanding of transition state structure can be obtained through a combination of experimental measurements of kinetic isotope effects (KIE) and computational chemistry methods (Schramm, 1998). The basis for the KIE approach is that incorporation of a heavy isotope, at a specific atom in a substrate molecule, will affect the enzymatic reaction rate to an extent that is correlated with the change in bond vibrational environment for that atom, in going from the ground state to the 

Synthesize the substrate with isotopic labels at all positions that may be perturbed during catalysis. 

Measure the KIE with high accuracy for each isotopically labeled form of the substrate. 

Use a combination of computational methods to determine bond lengths and bond angles, and electronic distributions at van der Waals surfaces, in the transition state. 

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