Fuzzy optimization for detecting enzyme targets of human uric acid metabolism.

MOTIVATION: Mathematical modeling and optimization have been used for detecting enzyme targets in human metabolic disorders. Such optimal drug design methods are generally differentiated as two stages, identification and decision-making, to find optimal targets. We developed a unified method named fuzzy equal metabolic adjustment to formulate an optimal enzyme target design problem for drug discovery. The optimization framework combines the identification of enzyme targets and a decision-making strategy simultaneously. The objectives of this algorithm include evaluations of the therapeutic effect of target enzymes, the adverse effects of drugs and the minimum effective dose (MED).
RESULTS: An existing generalized mass action system model of human uric acid (UA) metabolism was used to formulate the fuzzy optimization method for detecting two types of enzymopathies: hyperuricemia caused by phosphoribosylpyrophosphate synthetase (PRPPS) overactivity and Lesch-Nyhan syndrome. The fuzzy objectives were set so that the concentrations of the metabolites were as close as possible to the healthy levels. The target design included a diet control of ribose-5-phospahate (R5P). The diet control of R5P served as an extra remedy to reduce phosphate uptake entering the purine metabolic pathway, so that we could obtain a more satisfactory treatment than obtained for those without a diet control. Moreover, enhancing UA excretion resulted in an effective treatment of hyperuricemia caused by PRPPS overactivity. This result correlates with using probenecid and benbromazone, which are uricosuric agents present in current clinical medications. By contrast, the Lesch-Nyhan syndrome required at least three enzyme targets to cure hyperuricemia.