TY - JOUR
T1 - Conformational study on cyclic melanocortin ligands and new insight into their binding mode at the MC4 receptor
AU - Grieco, Paolo
AU - Brancaccio, Diego
AU - Novellino, Ettore
AU - Hruby, Victor J.
AU - Carotenuto, Alfonso
N1 - Funding Information:
The LC-MS and NMR spectral data were provided by Centro di Ricerca Interdipartimentale di Analisi Strumentale, Università degli Studi di Napoli “Federico II”. The assistance of the staff is gratefully appreciated. This work was supported by a grant from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (PRIN 2007), and a grant from the U.S. Public Health Service National Institutes of Health DK-17420.
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - DPC micelle solution
KW - Docking studies
KW - MC4 receptor
KW - Melanocortin peptides
KW - NMR spectroscopy
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U2 - 10.1016/j.ejmech.2011.05.038
DO - 10.1016/j.ejmech.2011.05.038
M3 - Article
C2 - 21652123
AN - SCOPUS:80052917925
SN - 0223-5234
VL - 46
SP - 3721
EP - 3733
JO - European journal of medicinal chemistry
JF - European journal of medicinal chemistry
IS - 9
ER -