Theoretical Study of Selective Human Melanocortin Receptors Agonists and Antagonists

Abstract

G-Protein Couple Receptors represent possibly the most important target class of proteins for drug discovery. GPCRs include many subcategories and this study focuses on melanocortin receptors. The experimentally determined NMR structures of two cyclic peptides analogues: SHU9119 (Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH₂), and MT-II (Ac-Nle-c[Asp- His-Phe-Arg-Trp-Lys]-NH₂) have been determined. We found that MTII is a potent and selective agonist for hMC4R and hMC3R but antagonist for hMC1R and hMCR5, whereas SHU-9119 is a better agonist for hMC1R and hMC5R but antagonist for hMC4R and hMC3R. These results are consistent with the experimental data. Another part of the study describes the interactions between each ligand and receptor. Arg⁶ of the ligands was found to have the most interactions with every receptor which suggests that is critical important for binding. The active site residues D121 and D117 of hMCR1 had the most interactions with both ligands. In hMC3R, D121 and D117 interacted the most with MT-II and SHU9119. In hMC4R, residue D122 had more interaction with MT-II than SHU9119, In hMC5R, the residue D119 interacted the most with either MT-II or SHU9119, whereas. Residue W251 interacted with SHU9119 only. Also, residues F254 interacted more with MT-II than in SHU9119.