Abstract
The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems.
Highlights
The agonistic proopiomelanocortin-derived neuropeptides α, β, and γ-melanocyte-stimulating hormone (α, β, γ-MSH), the adrenocorticotropic hormone (ACTH) and the inverse agonistic agouti-related peptide (AgRP) are ligands for five closely related melanocortin receptors (MC1-5R), a subgroup of class A G-protein coupled receptors (GPCRs) (Gantz et al, 1993; Cone, 2005, 2006; Dores et al, 2014)
It is reported that the ligand MCL0129 is selective among the hMCR subtypes (Sabban and Serova, 2018) and we identified residues in the suggested human MC4R (hMC4R) ligand binding site that are similar, identical, or specific compared to hMC1R, hMC2R, hMC3R or hMC5R (Supplementary Figure S1)
Spontaneous binding of the selective melanocortin-4 receptor (MC4R) non-peptide antagonist MCL0129 (1-[(1S)-1-(4fluorophenyl)-2-[4-[4-(2-methoxynaphthalen-1-yl)butyl] piperazin-1-yl]ethyl]-4-propan-2-ylpiperazine) was observed during 5 μs unbiased molecular dynamics (MDs) simulation (Chaki et al, 2003). These simulations were analyzed to (i) elucidate the pathway and mechanism of MCL0129 binding to hMC4R, (ii) detect binding intermediates and calculate binding affinities of MCL0129 using metadynamics simulations and to (iii) explore the basic structural features of hMC4R in a stabilized antagonist-bound inactive state
Summary
The agonistic proopiomelanocortin-derived neuropeptides α-, β-, and γ-melanocyte-stimulating hormone (α-, β-, γ-MSH), the adrenocorticotropic hormone (ACTH) and the inverse agonistic agouti-related peptide (AgRP) are ligands for five closely related melanocortin receptors (MC1-5R), a subgroup of class A G-protein coupled receptors (GPCRs) (Gantz et al, 1993; Cone, 2005, 2006; Dores et al, 2014). The melanocortin system is involved in a plethora of physiological functions, including pigmentation, steroidogenesis, energy homeostasis, and sexual function (Cone, 2006; Rodrigues et al, 2015). The ligand ACTH acts on MC2R (Liang et al, 2013) and is involved in controlling glucocorticoid levels (Fridmanis et al, 2017). The exact physiological role of the MC3R is not clear.
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