Basic Information
ID: ALA4765463
Journal: J Med Chem
Title: Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure†.
Authors: Martin C,Gimenez LE,Williams SY,Jing Y,Wu Y,Hollanders C,Van der Poorten O,Gonzalez S,Van Holsbeeck K,Previti S,Lamouroux A,Zhao S,Tourwé D,Stevens RC,Cone RD,Ballet S
Abstract: The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle, DNal(2'), and Trp residues in SHU-9119, as well as the amide linkage between the Asp and Lys side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.
CiteXplore: 33190475
DOI: 10.1021/acs.jmedchem.0c01620
Patent ID: ┄
Associated Items: Associated Bioactivities Associated Assays Associated Compounds Associated Targets