Computer-Based Strategy for Modeling the Interaction of AGRP and Related Peptide Ligands with the AGRP-Binding Site of Murine Melanocortin Receptors

The hypothesis that the interaction of agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4R) modulates feeding behavior in humans has stimulated the synthesis of conformationally constrained peptides, peptoids and small molecules in efforts to identify novel compounds that can potentially be used in the clinical treatment of obesity and related eating disorders. In addition, the availability of a high-resolution NMR structure for the MC4R-binding domain of AGRP, and studies employing site-specific murine MC4R mutants have identified key intermolecular AGRP / MC4R interactions. It is therefore surprising that only one, relatively unsophisticated, computer-based study has been reported to obtain a model for the AGRP / mMC4R complex. In this review we outline computer-based strategies for building models of the AGRP / mMC4R and related peptide / mMC4R complexes, and illustrate the strengths and limitations of sophisticated molecular dynamics methods in obtaining information that might form the basis of rational efforts to discover novel drugs that selectively interact with melanocortin receptors.