The Computer-Automated Structure Evaluation (CASE) methodology has been applied to a set of flavonoids and other structurally related compounds tested for glyoxalase 1 enzyme inhibition. CASE identified several structural features believed to be responsible for activity. A total of five fragments were isolated. The most important structural feature is the alpha-hydroxy-alpha, beta-unsaturated carbonyl group attached to a fused ring carbon atom. The fragment tautomerizes into a transition state analog of the substrate of the enzyme. Five tested compounds initially removed from the database were submitted to CASE in the predictive mode. The predictions generally matched the tested values for enzyme inhibition. A set of chromones and phenyl-pyrones, although untested, were also submitted to CASE. CASE predicts that, as a class of compounds, chromones would be more effective inhibitors than phenyl-pyrones. (Copyright (c) by The American Society for Pharmacology and Experimental Therapeutics.)