Conformational study on cyclic melanocortin ligands and new insight into their binding mode at the MC4 receptor

Paolo Grieco, Diego Brancaccio, Ettore Novellino, Victor J. Hruby, Alfonso Carotenuto

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The melanocortin receptors are involved in many physiological functions, including pigmentation, sexual function, feeding behavior, and energy homeostasis, making them potential targets to treat obesity, sexual dysfunction, etc. Understanding the basis of the ligand-receptor interactions is crucial for the design of potent and selective ligands for these receptors. The conformational preferences of the cyclic melanocortin ligands MTII (Ac-Nle 4-c[Asp 5-His 6-DPhe 7-Arg 8-Trp 9-Lys 10]-NH 2) and SHU9119 (Ac-Nle 4-c[Asp 5-His 6-DNal(2′) 7-Arg 8-Trp 9-Lys 10]-NH 2), which show agonist and antagonist activity at the h-MC4R, respectively, were comprehensively investigated by solution NMR spectroscopy in different environments. In particular, water and water/DMSO (8:2) solutions were used as isotropic solutions and an aqueous solution of DPC (dodecylphosphocholine) micelles was used as a membrane mimetic environment. NMR-derived conformations of these two ligands were docked within h-MC4R models. NMR and docking studies revealed intriguing differences which can help explain the different activities of these two ligands.

Original languageEnglish (US)
Pages (from-to)3721-3733
Number of pages13
JournalEuropean journal of medicinal chemistry
Volume46
Issue number9
DOIs
StatePublished - Sep 1 2011

Keywords

  • DPC micelle solution
  • Docking studies
  • MC4 receptor
  • Melanocortin peptides
  • NMR spectroscopy

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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