Abstract
The solution structures and inter-molecular interaction of the cyclic melanocortin antagonists SHU9119, JKC363, HS014, and HS024 with receptor molecules have been determined by NMR spectroscopy and molecular modeling. While SHU9119 is known as a nonselective antagonist, JKC363, HS014, and HS024 are selective for the melanocortin subtype-4 receptor (MC4R) involved in modulation of food intake. Data from NMR and molecular dynamics suggest that the conformation of the Trp9 sidechain in the three MC4R-selective antagonists is quite different from that of SHU9119. This result strongly supports the concept that the spatial orientation of the hydrophobic aromatic residue is more important for determining selectivity than the presence of a basic, "arginine-like" moiety responsible for biological activity. We propose that the conformation of hydrophobic residues of MCR antagonists is critical for receptor-specific selectivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Drug Interactions
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Hydrophobic and Hydrophilic Interactions
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Magnetic Resonance Spectroscopy
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Melanocyte-Stimulating Hormones / chemical synthesis
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Melanocyte-Stimulating Hormones / chemistry*
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Melanocyte-Stimulating Hormones / pharmacology
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Models, Molecular
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Molecular Sequence Data
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Peptides, Cyclic / chemical synthesis
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Peptides, Cyclic / chemistry*
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Peptides, Cyclic / pharmacology
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Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
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Receptor, Melanocortin, Type 4 / drug effects
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Receptors, Melanocortin / antagonists & inhibitors*
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Receptors, Melanocortin / drug effects
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Sensitivity and Specificity
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Solutions / chemistry
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Structure-Activity Relationship
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beta-MSH / chemical synthesis
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beta-MSH / chemistry
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beta-MSH / pharmacology
Substances
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11-Mrp-14-Nal-18-Cys-22-Asp-beta-MSH(11-22)NH2
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Peptides, Cyclic
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Receptor, Melanocortin, Type 4
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Receptors, Melanocortin
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Solutions
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beta-MSH
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SHU 9119
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Melanocyte-Stimulating Hormones