title: Molecular dynamics, dynamic site mapping, and highthroughput virtual screening on leptin and the Ob receptor as anti-obesity target.
abstract: Body weight control is a mechanism finely regulated by several hormonal, metabolic, and nervous pathways. The leptin receptor (Ob-R) 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, and under normal circumstances, circulating levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neurocircutry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased concentrations lead to opposite effects. Therefore rational design of leptin agonists constitute an appealing challenge in the battle against obesity. In this study, we performed protein-protein docking among the re-built crystal structure of leptin and leptin binding domain (LBD). The obtained complex was used as a starting point to carry out nanosecond-scale molecular dynamics simulations to characterize the key regions in terms of physical-chemical features involved in the protein-protein interaction (dynamic site mapping filtered by means multivariate analysis) and used to carry out a HTVS. The main goal of this study was to suggest guidelines for the rational drug design of new agonists of leptin. Identified hits could be a consistent starting point to carry out in vitro testing.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tutone
authors.forename: Licia
authors.initials: L
authors.lastname: Pantano
authors.forename: Antonino
authors.initials: A
authors.lastname: Lauria
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Almerico
mesh_terms: D019440:Anti-Obesity Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020738:Leptin / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D015999:Multivariate Analysis; D011485:Protein Binding; D011487:Protein Conformation; D054411:Receptors, Leptin / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D020738:Leptin; D054411:Receptors, Leptin