Molecular dynamics, dynamic site mapping, and highthroughput virtual screening on leptin and the Ob receptor as anti-obesity target

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Abstract

Body weight control is a mechanism finely regulatedby several hormonal, metabolic, and nervous pathways.The leptin receptor (Ob-R) is crucial for energy homeostasisand regulation of food uptake. Leptin is a 16 kDa hormonethat is mainly secreted by fat cells into the bloodstream, andunder 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 rebuilt 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 physicalchemical 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 newagonists of leptin. Identified hits could be a consistent starting point to carry out in vitro testing.
Lingua originaleEnglish
pagine (da-a)1-10
Numero di pagine10
RivistaJournal of Molecular Modeling
Volume20
Stato di pubblicazionePublished - 2014

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry

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