W0157

Structure-Based Drug Design of Aldose and Aldehyde Reductases. Ossama El-Kabbani and Mark von Itzstein, Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, VIC 3052 Australia

Recent studies have identified two enzymes, aldose and aldehyde reductases, as potential drug targets to alleviate some of the degenerative problems associated with the complications of diabetes. To date, none of the currently available inhibitors has been approved for clinical use due to undesirable side effects. Based on the recent ternary structures of the enzymes, we have designed mimetics of the nicotinamide-ribose portion of NADPH which possess components of both coenzyme and inhibitor molecules, and utilize the maximum interactions between the enzymes and the bound ligands. The nicotinamide mimetic molecules were modeled in the coenzyme and inhibitor-binding sites of the reductases. The carboxylate, amide and ribose moieties of

the nicotinamide mimetics were hydrogen bonded to the inhibitor and coenzyme-binding residues. Synthesis and biological evaluation of newly designed compounds are currently in progress.