ABSTRACT
Aldose reductase is an ~36 kDa enzyme that catalyzes the reduction of a wide range of carbonyl-containing compounds to their corresponding alcohols. Most previous inhibition studies reported noncompetitive and/or uncompetitive inhibition patterns when aldose reductase inhibitors were examined in the forward direction, inhibition of NADPH-dependent aldehyde reduction. The problem of structure-based drug design for Aldose reductase (ALR2) and the drug-design effort in general is compounded by the fact that this enzymes is a member of a large family of aldo-keto reductases with overlapping substrate specificity. Structures of several other members of the aldo-keto reductase family have also been determined. Increased in vivo potency is likely to be derived from the specific inhibition of ALR2 that would entail the avoidance of other members of the aldo-keto reductase family. Inhibition studies involving ALR2 have indicated noncompetitive inhibition for virtually all compounds examined to date when the forward reaction is monitored.
