Homology Modeling and Docking Studies Identify Subtype-Specific Characteristics of Melanocortin Receptor Activation

Abstract

Melanocortin receptors (MCRs) belong to the family of G protein-coupled receptors (GPCRs), and the five subtypes of MCRs (MC1R, MC2R, MC3R, MC4R, and MC5R) are implicated in diverse physiological processes such as pigmentation, food intake, and energy homeostasis. Because of their physiological importance, MCRs are natural targets for drug development. It is known that synthetic cyclic analogues of natural MCR hormones have the potential for pharmaceutical applications. However, 1) no current structures exist for MCRs and 2) the synthetic cyclic peptides possess little specificity for MCR subtypes, making identification of structural motifs in receptor-ligand binding extremely difficult. Our hypothesis is that MCR activity is determined by specific intermolecular interactions of ligand side chains with amino acid residues of the melanocortin receptor, while the selectivity of the ligands towards different subtypes of MCRs is controlled by conformational restraints of ligand backbones. Identification of general characteristics of MCR-ligand interactions will facilitate intelligent design of modified ligand structures that lead to MCR subtype specificity. To test this hypothesis, we developed homology models of the different MCR subtypes and conducted docking studies of a known agonist (Melanotan-II) and antagonist (SHU-9119) on each MCR model, in order to characterize the respective binding affinities of each receptor-ligand complex. Our results show that agonists and antagonists have a common set of binding characteristics along with interactions that are unique to each ligand that can be directly related to their function. The ability to accurately characterize unique structural interactions between known MCR agonists and antagonists is the first step in developing the ability to design effective, subtype-specific therapeutic agents of melanocortin receptors.