Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach.

ABSTRACT: Human melanocortin-4 receptor (hMC4R) mutations have been implicated as the cause for about 6-8% of all severe obesity cases. Drug-like molecules that are able to rescue the functional activity of mutated receptors are highly desirable to combat genetic obesity among this population of patients. One such molecule is the selective MC4R agonist RM-493 (setmelanotide). While this molecule has been shown to activate mutated receptors with 20-fold higher potency over the endogenous agonist, little is known about its binding mode and how it effectively interacts with hMC4R despite the presence of mutations. In this study, a MC4R homology model was constructed based on the X-ray crystal structure of the adenosine A2A receptor in the active state. Four MC4R mutations commonly found in genetically

SUBMITTER: Falls BA 

PROVIDER: S-EPMC6374207 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature