The aldose reductase inhibitor site

Evidence linking the enzyme aldose reductase (alditol:NADP+ oxidoreductase, EC 1.1.1.21) to the pathogenesis of several diabetic complications is rapidly mounting. The results of several animal studies combined with preliminary reports of ongoing clinical trials indicate that inhibition of aldose reductase produces a beneficial effect against such diabetic complications as neuropathy, cataract, corneal epitheliopathy, retinopathy, microangiopathy, and possibly nephropathy. The observations that aldose reductase inhibitors appear to provide a new direct mode of treatment for the control of diabetic complications--a method independent of the insulin-related control of blood glucose levels--has spurred interest in the development of more potent and selective inhibitors. That goal can be more easily realized through an understanding of how these inhibitors interact with the aldose reductase protein. This requires insight into the steric and electronic requirements of both the inhibitors and the enzyme site where they bind (inhibitor site). Through the use of computer molecular modeling, molecular orbital calculations, known structure-activity relationships (SAR), protein modification reagents, and irreversible inhibitors, specific structural, and electronic similarities among the apparently structurally diverse aldose reductase inhibitors (ARIs) have been observed. In turn, these studies have led us to postulate the pharmacophor requirements of the ARI site.