Use of Transition-State Theory in the Development of Bioactive Molecules

Abstract

The application of transition state theory to enzyme catalysis is presented in terms of mechanistic and energetic approaches. These treatments emphasize the rationale of using transition state analogs as bioactive molecules. Included in this chapter are some criteria for determining if a compound is a transition state analog. A hypothesis is then presented that the initial binding of some insecticidal carbamates and organophosphates to acetylcholinesterase is dependent in part upon their mimicking the transition state configuration of acetylcholine. As an indication of how transition state theory could be applied to problems in agricultural chemistry, we present data from this laboratory that some trifluoromethylketone inhibitors of insect juvenile hormone esterase(s) are transition state mimics and extend this argument by applying a quantitative structure-activity relationship approach to these analogs.