Aldose reductase and protein tyrosine phosphatase 1B inhibitors as a promising therapeutic approach for diabetes mellitus

Diabetes mellitus is a metabolic disease characterized by high blood glucose levels and usually associated with several chronic pathologies. Aldose reductase and protein tyrosine phosphatase 1B enzymes have identified as two novel molecular targets associated with the onset and progression of type II diabetes and related comorbidities. Although many inhibitors against these enzymes have already found in the field of diabetic mellitus, the research for discovering more effective and selective agents with optimal pharmacokinetic properties continues. In addition, dual inhibition of these target proteins has proved as a promising therapeutic approach. A variety of diverse scaffolds are presented in this review for the future design of potent and selective inhibitors of aldose reductase and protein tyrosine phosphatase 1B based on the most important structural features of both enzymes. The discovery of novel dual aldose reductase and protein tyrosine phosphatase 1B inhibitors could be effective therapeutic molecules for the treatment of insulin-resistant type II diabetes mellitus. The methods used comprise a literature survey and X-ray crystal structures derived from Protein Databank (PDB). Despite the available therapeutic options for type II diabetes mellitus, the inhibitors of aldose reductase and protein tyrosine phosphatase 1B could be two promising approaches for the effective treatment of hyperglycemia and diabetes-associated pathologies. Due to the poor pharmacokinetic profile and low in vivo efficacy of existing inhibitors of both targets, the research turned to more selective and cell-permeable agents as well as multi-target molecules.

Keywords: Aldose reductase; Diabetes mellitus; Diabetic complications; Dual inhibitors; Insulin resistance; Protein tyrosine phosphatase 1B; Selectivity.