Structure-based discovery of potent and selective melatonin receptor agonists

Area of Science:

• Pharmacology and Medicinal Chemistry
• Structural Biology
• Neuroscience

Background:

• Melatonin receptors (MT1 and MT2) regulate circadian rhythms and are therapeutic targets for sleep disorders, mood disorders, type-2 diabetes, and cancer.
• Discovering novel, potent, and selective MT receptor ligands is crucial for developing new treatments.

Purpose of the Study:

• To identify novel chemotypes acting as agonists at melatonin receptors (MT1 and MT2) using structure-based virtual screening.
• To evaluate the potency, selectivity, and signaling bias of newly discovered MT receptor agonists.

Main Methods:

• Large-scale structure-based virtual screening utilizing high-resolution 3D crystal structures of agonist-bound MT receptors.
• Experimental testing of 62 screening candidates for MT receptor agonism.
• Assays to determine compound potency (EC50), selectivity (MT2 over MT1), and biased signaling (arrestin recruitment and Gi signaling).

Main Results:

• Discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors; compound 21 achieved an EC50 of 0.36 nM.
• Six identified compounds exhibited selectivity for MT2 over MT1 receptors.
• Two potent agonists (compounds 21 and 28) showed reduced arrestin recruitment at MT2, and compound 37 displayed absent Gi signaling at MT1, indicating biased signaling.

Conclusions:

• The study successfully identified novel MT receptor agonists with significant potency and selectivity using structure-based drug design.
• The findings demonstrate the potential for biased signaling modulation at MT receptors, opening new therapeutic avenues.
• The agonist-bound orthosteric pocket of MT receptor structures is validated as a suitable target for structure-based discovery of selective agonists.