Marco Tutone, Antonino Lauria and Anna Maria Almerico Pages 136 - 145 ( 10 )
The OB-receptor or leptin receptor (LR) is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells into the bloodstream. Under normal circumstances, circulating leptin levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neuro-circuitry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased leptin concentrations lead to opposite effects. Therefore, rational design of leptin agonists/antagonists could be an appealing challenge in the battle against obesity. The Leptin/LR interactions have been studied in several works by means of different molecular modelling approaches, spreading from homology modelling to manual docking. No small molecules have ever been proposed as agonists of the Ob receptor but researchers’ efforts focused only on leptin-related synthetic peptides as receptor antagonists and on peptidomimetics. In this review we try to track a timeline of obtained in silico information to clarify the mechanism of interaction between leptin and its receptor, together to summarize the more recent efforts to propose new drugs usable in anti-obesity therapy. Final considerations could be useful starting points for the rational drug design of new lead compounds.
Homology modelling, leptin, leptin receptor, leptin receptor agonists/antagonists, molecular modelling, protein/protein docking, obesity.
, , Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Universita di Palermo, Via Archirafi 32, 90123 Palermo.