Query generation to search for inhibitors of enzymatic reactions.

A method for the generation of intermediates of enzyme-catalyzed reactions is presented. These intermediates can be used as three-dimensional structural queries for searching for inhibitors of enzymatic reactions. The intermediates can be considered as being structurally quite close to transition-state analogues. For this application, a database containing detailed chemical information on metabolic reactions is used. The likely three-dimensional structure of the intermediates of enzyme-catalyzed reactions can be generated from the information in the database. For three reactions catalyzed by the enzymes AMP deaminase (EC code 3.5.4.6), triose phosphate isomerase (EC code 5.3.1.1), and arginase II (EC code 3.5.3.1), we show how a 3D model of these intermediates can be superimposed onto known inhibitors of these enzymes by a program that uses a genetic algorithm. For this, we test different methods for the superimposition using information on the enzymatic binding site, using information on physicochemical properties calculated from the molecular structure, or without having any information in the superimposition process. We show that these inhibitors are most similar to the corresponding intermediates regarding the 3D structure.