CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists.

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Computational Chemistry

Background:

• Melanocortin receptors (MCRs) are crucial in physiological and pathological processes.
• Developing selective MCR agonists/antagonists is a key goal in medicinal chemistry.
• Melanotan II (MT-II) is a potent but unselective MCR agonist.

Purpose of the Study:

• To design and synthesize novel peptide analogs of MT-II with improved selectivity.
• To investigate the structure-activity relationships of modified peptides with MCRs.
• To explore the conformational effects of different cyclization strategies on peptide affinity.

Main Methods:

• Chemical Linkage of Peptide onto Scaffolds strategy was employed.
• Lactam cyclization in MT-II was replaced with xylene-derived thioethers.
• Binding affinities to human MCRs (hMCRs) were measured.
• Enhanced sampling molecular dynamics simulations were performed.
• A peptide-receptor complex model was built using cryo-EM data.

Main Results:

• Newly designed peptides exhibited binding affinities in the nanomolar to sub-micromolar range.
• A correlation between linker structure and hMCR affinity was observed.
• Compound 5 demonstrated significant functional selectivity for hMC1R over other hMCRs.
• Molecular dynamics simulations elucidated the impact of cyclization on peptide conformation and hMC1R affinity.

Conclusions:

• The novel cyclization strategy successfully generated peptides with modulated affinity and selectivity for hMCRs.
• Compound 5 represents a promising selective hMC1R ligand.
• Computational modeling provides insights into the molecular basis of selective receptor recognition.