Dissecting the Activity of Catechins as Incomplete Aldose Reductase Differential Inhibitors through Kinetic and Computational Approaches

Simple Summary The increased glucose levels occurring in diabetes lead to several metabolic alterations responsible for the onset of the so-called diabetic complications, which include nephropathies, neuropathies, retinopathies, and cataract. An increased flux of glucose through the polyol pathway is considered the most relevant among these alterations. For this reason, the block of the polyol pathway, through the inhibition of the enzyme aldose reductase, is considered a valuable strategy to impair the onset of diabetic complications. However, aldose reductase also exerts a beneficial effect inside cells, since it can remove toxic aldehydes. Thus, to ameliorate the outcome of the use of aldose reductase inhibitors, the use of "differential inhibitors" has been proposed. These inhibitors should block the catalytic activity depending on the substrate the enzyme is working on, thus preserving the detoxifying action of the enzyme. In this work, derivatives of catechins are analyzed to evaluate their inhibitory action on aldose reductase. The study was conducted both in vitro on the isolated enzyme and in silico through a computational approach. Results demonstrated that gallocatechin gallate and catechin gallate act as differential inhibitors and that this action may be linked to an incomplete inhibitory effect. The inhibition of aldose reductase is considered as a strategy to counteract the onset of both diabetic complications, upon the block of glucose conversion in the polyol pathway, and inflammation, upon the block of 3-glutathionyl-4-hydroxynonenal reduction. To ameliorate the outcome of aldose reductase inhibition, minimizing the interference with the detoxifying role of the enzyme when acting on toxic aldehydes, "differential inhibitors", i.e., molecules able to inhibit the enzyme depending on the substrate the enzyme is working on, has been proposed. Here we report the characterization of different catechin derivatives as aldose reductase differential inhibitors. The study, conducted through both a kinetic and a computational approach, highlights structural constraints of catechin derivatives relevant in order to affect aldose reductase activity. Gallocatechin gallate and catechin gallate emerged as differential inhibitors of aldose reductase able to preferentially affect aldoses and 3-glutathionyl-4-hydroxynonenal reduction with respect to 4-hydroxynonenal reduction. Moreover, the results highlight how, in the case of aldose reductase, a substrate may affect not only the model of action of an inhibitor, but also the degree of incompleteness of the inhibitory action, thus contributing to differential inhibitory phenomena.