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 obese patients and known to effect ligand binding in vitro were introduced into the constructed model. RM-493 was then docked into the wild-type and mutated models in order to better elucidate the possible binding modes for this promising drug candidate and assess how it may be interacting with MC4R to effectively activate receptor polymorphisms. The results reflected the orthosteric interactions of both the endogenous and synthetic ligands with the MC4R, which is supported by the site-directed mutagenesis studies. Meanwhile it helped explain the decremental affinity and potency of these ligands with the receptor polymorphisms. More significantly, our findings indicated that the structural characteristics of RM-493 may allow for enhanced receptor-ligand interactions, particularly through those with the putative allosteric binding sites, which facilitated the ligand to stabilize the active state of native and mutant MC4Rs to maintain reasonably high affinity and potency.

Setmelanotide, a Novel, Selective Melanocortin Receptor-4 Agonist Exerts Anti-inflammatory Actions in Astrocytes and Promotes an Anti-inflammatory Macrophage Phenotype

“…Future studies are warranted to study the therapeutic efficacy of setmelanotide in experimental animal models of MS and whether astrocyte-specific MC4R knockout is able to block these effects. Setmelanotide has shown to be well-tolerated in a phase 2 clinical trial in obese individuals with a rare genetic disorder, and mouse knock-out studies have shown that setmelanotide-associated weight loss is regulated via MC4R, which is mainly attributed to MC4R neurons of the hypothalamus (52, 53). Our findings could set the stage for setmelanotide as a new therapeutic for inflammation associated neurodegeneration in MS.…”

Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21

“…C3aR1 (NP_033909.1) were based on the structural conserved regions identified from multiple sequence alignment of C3aR1 and C5aR1 across various mammalian species. The approach was based on our earlier approach (Zhang et al, 2005) that has been widely adopted in other GPCR studies (Ahmed et al, 2014; Falls and Zhang, 2018). The sequence alignment used for the homology modeling is shown in the Figure S8.…”

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

“…Although in vitro receptor affinity and activity data show that setmelanotide also exhibits agonist activity at the MC1R, MC3R, and MC5R, much higher concentrations (at least 20‐fold) of setmelanotide are needed for activation of other melanocortin receptors than for MC4R . In 2017, setmelanotide entered phase 3 clinical trials in patients with obesity bearing MC4R mutations . In a phase 2, randomized, double‐blind, placebo‐controlled pilot trial of setmelanotide (NCT02311673), patients with PWS (aged 16‐65 years) treated with the highest dose and for the longest period of time experienced clinically meaningful weight loss despite only modest improvement in hyperphagia .…”