Identifying Human PTP1B Enzyme Inhibitors from Marine Natural Products: Perspectives for Developing of Novel Insulin-Mimetic Drugs.
Marcello CasertanoMassimo GenoveseLucia PiazzaFrancesco BalestriAntonella Del CorsoAlessio VitoPaolo PaoliAlice SantiConcetta ImperatoreMarialuisa MennaPublished in: Pharmaceuticals (Basel, Switzerland) (2022)
Diabetes mellitus (DM) represents a complex and multifactorial disease that causes metabolic disorders with acute and long-term serious complications. The onset of DM, with over 90% of cases of diabetes classified as type 2, implies several metabolic dysfunctions leading to consider DM a worldwide health problem. In this frame, protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) are two emerging targets involved in the development of type 2 diabetes mellitus (T2DM) and its chronic complications. Herein, we employed a marine-derived dual type inhibitor of these enzymes, phosphoeleganin, as chemical starting point to perform a fragment-based process in search for new inhibitors. Phosphoeleganin was both disassembled by its oxidative cleavage and used as model structure for the synthesis of a small library of functionalized derivatives as rationally designed analogues. Pharmacological screening supported by in silico docking analysis outlined the mechanism of action against PTP1B exerted by a phosphorylated fragment and a synthetic simplified analogue, which represent the most potent inhibitors in the library.
Keyphrases
- glycemic control
- type diabetes
- molecular docking
- endothelial cells
- public health
- protein protein
- risk factors
- healthcare
- cardiovascular disease
- drug induced
- mental health
- weight loss
- liver failure
- insulin resistance
- respiratory failure
- risk assessment
- high resolution
- transcription factor
- anti inflammatory
- aortic dissection
- binding protein
- simultaneous determination
- pluripotent stem cells
- acute respiratory distress syndrome
- solid phase extraction