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

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• 作者：Marco Tutone ; Licia Pantano ; Antonino Lauria…
• 关键词：Dynamic Site Mapping ; HTVS ; Leptin ; Molecular Dynamics ; Obesity ; Protein/protein docking ; Multivariate analysis ; Ob Receptor
• 刊名：Journal of Molecular Modeling
• 出版年：2014
• 出版时间：May 2014
• 年：2014
• 卷：20
• 期：5
• 全文大小：3,597 KB
• 参考文献：1. Heshka, J, Jones, P (2001) A role for dietary fat in leptin receptor, Ob-Rb, function. Life Sci 69: pp. 987-1003 CrossRef
  2. Fruhbeck, G (2001) A heliocentric view of leptin. Proc Nutr Soc 60: pp. 301-318 CrossRef
  3. Zhang, FM, Basinski, M, Beals, J, Briggs, S, Churgay, L, Clawson, D, Marchi, R, Furman, T, Hale, J, Hsiung, H, Schoner, B, Smith, D, Zhang, XY, Wery, J, Shevitz, R (1997) Crystal structure of the obese leptin-E100. Nature 387: pp. 206-209 CrossRef
  4. Tartaglia, LA, Dembski, M, Weng, X, Deng, N, Culpepper, J, Devos, R, Richards, GJ, Campfield, LA, Clark, FT, Deeds, J (1995) Identification and expression cloning of a leptin receptor, Ob-R. Cell 83: pp. 1263-1271 CrossRef
  5. Fong, TM, Huang, RR, Tota, MR, Mao, C, Smith, T, Varnerin, J, Karpitskiy, VV, Krause, JE, Ploeg, LH (1998) Localization of leptin binding domain in the leptin receptor. Mol Pharmacol 53: pp. 234-240
  6. Sandowski, Y, Raver, N, Gussakovsky, EE, Shochat, S, Dym, O, Livnah, O, Rubinstein, M, Krishna, R, Gertler, A (2002) Subcloning, expression, purification, and characterization of recombinant human leptin-binding domain. J Biol Chem 277: pp. 46304-46309 CrossRef
  7. Iserentant, H, Peelman, F, Defeau, D, Vandekerckhove, J, Zabeau, L, Tavernier, J (2005) Mapping of the interface between leptin and the leptin receptor CRH2 domain. J Cell Sci 118: pp. 2519-2527 CrossRef
  8. Peelman, F, Beneden, K, Zabeau, L, Iserentant, H, Ulrichts, P, Defeau, D, Verhee, A, Catteeuw, D, Elewaut, D, Tavernier, J (2004) Mapping of the leptin binding sites and design of a leptin antagonist. J Biol Chem 279: pp. 41038-41046 CrossRef
  9. Peelman, F, Iserentant, H, Smet, AS, Vandekerckhove, J, Zabeau, L, Tavernier, J (2006) Mapping of binding site III in the leptin receptor and modeling of a hexameric leptin-leptin receptor complex. J Biol Chem 281: pp. 15496-15504 CrossRef
  10. Hiroike, T, Higo, J, Jingami, H, Toh, H (2000) Homology modeling of human leptin/leptin receptor complex. Biochem Biophys Res Commun 275: pp. 154-158 CrossRef
  11. Zabeau, L, Defeau, D, Iserentant, H, Vandekerckhove, J, Peelman, F, Tavernier, J (2005) Leptin receptor activation depends on critical cysteine residues in its fibronectin type III subdomains. J Biol Chem 280: pp. 22632-22640 CrossRef
  12. Zabeau, L, Verhee, A, Catteeuw, D, Faes, L, Seeuws, S, Decruy, T, Elewaut, D, Peelman, F, Tavernier, J (2012) Selection of non-competitive leptin antagonists using a random nanobody-based approach. Biochem J 441: pp. 425-434 CrossRef
  13. Carpenter, B, Hemsworth, G, Wu, Z, Maamra, M, Strasburger, C, Ross, R, Artymiuk, P (2012) Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin-antagonism by a monoclonal antibody. Structure 20: pp. 487-497 CrossRef
  14. Tutone, M, Lauria, A, Almerico, AM (2014) Leptin and the ob-receptor as anti-obesity target: recent in silico advances in the comprehension of the protein-protein interaction and rational drug design of anti-obesity lead compounds. Curr Pharm Des 20: pp. 136-145 CrossRef
  15. Lauria, A, Tutone, M, Barone, G, Almerico, AM (2014) Multivariate analysis in the identification of biological targets for designed molecular structures: the BIOTA protocol. Eur J Med Chem.
  16. Lauria, A, Terenzi, A, Gentile, C, Martorana, A, Gennaro, G, Barone, G, Almerico, AM (2014) In silico, spectroscopic, and biological insights on
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

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. Figure Leptin and the Ob receptor