Molecular interactions of diabetes medications with alzheimer's related targets by molecular docking.

Abstract

Diabetes, a prevalent chronic disease known for its complications such as cardiovascular issues, eye damage, and neuropathy, has increasingly been linked to an elevated risk of Alzheimer's disease and cognitive impairment. Individuals with diabetes are approximately twice as likely to experience cognitive dysfunction compared to the general population. This heightened risk is potentially mediated by factors such as hypoglycemic episodes, which can negatively impact brain function, particularly the hippocampus, a key region for memory. Furthermore, shared molecular and cellular characteristics between diabetes and Alzheimer's, such as the role of insulin in amyloid plaque formation, suggest a direct link between insulin resistance in the brain and the development of Alzheimer's-related pathology. This study investigates the potential of two commonly prescribed diabetes medications, Ertugliflozin and Sitagliptin, to impact Alzheimer's disease-related factors. Ertugliflozin, an SGLT2 inhibitor, lowers blood glucose by increasing glucose excretion via the kidneys, while Sitagliptin, a DPP-4 inhibitor, enhances insulin secretion and reduces glucagon secretion by preventing the breakdown of incretin hormones. Molecular docking was performed to assess the interaction of these drugs with five key targets implicated in Alzheimer's disease: amyloid-β, β-secretase (BACE1), γ-secretase, and acetylcholinesterase (AChE). The aim was to determine whether Ertugliflozin and Sitagliptin exhibit inhibitory effects on these Alzheimer's-related targets, suggesting a potential dual role beyond their established glucose-regulating mechanisms in diabetes. In this study, Metformin was utilized as the positive control ligand. Docking analysis revealed that Ertugliflozin and Sitagliptin exhibited the highest molecular affinity for γ-secretase (PDB code: 6iyc), followed by favorable interactions with β-secretase (PDB code: 1fkn) and amyloid-β (PDB code: 1iyt). Notably, Ertugliflozin showed notable interactions with acetylcholinesterase (PDB code: 1eve), whereas Sitagliptin showed no significant interaction with acetylcholinesterase. These findings suggest that Ertugliflozin and Sitagliptin, commonly used for diabetes management, may also influence factors implicated in Alzheimer's disease. By potentially inhibiting these factors, the drugs could exhibit a dual action, benefiting both diabetes and Alzheimer's. Further in vivo and clinical studies are needed to confirm these observations.