Melatonin targets two high-affinity receptors, MT1 and MT2, that belong to the G protein-coupled receptor (GPCR) superfamily (1,2). Drugs acting on melatonin receptors are subscribed for circadian disorders (jet lag, shift work, etc.), insomnia and major depression (3). All marketed drugs are non-selective agonists targeting both receptor types so far. Despite large chemical synthesis campaigns over the last 20 years, the pharmacology of melatonin receptors remains poorly explored with few inverse agonistic and signaling pathway-biased compounds and few selective compounds, in particular for the MT1 type (2,4). This lack of pharmacological tools goes along with a rather poor diversity in terms of chemical scaffolds currently available (5). Put into this context, a virtual screening looked like a very promising approach to increase the diversity of chemical scaffolds for melatonin receptors, especially now that the crystal structure of the MT1 receptor has been solved (6). The outcome of the virtual screening study performed by Stein et al. (7) met these high expectations. Overall, 15 new chemical scaffolds were identified from the primary docking of over 150 million virtual molecules (7). Some of the primary hits had pEC50 values around 1nM, which is remarkable. In terms of functional properties, primary hits and derivatives showed agonistic and inverse agonistic properties with or without selectivity for MT1 and MT2. Two MT1 selective inverse agonists were further validated in vivo regarding their effects on circadian rhythm parameters in mice under free-running conditions, as well as using an experimental re-entrainment protocol corresponding to an ‘east-bound’ jet lag paradigm.
This study is not only of great value for the melatonin receptor field but will also encourage virtual screening approaches on other GPCRs for which high-resolution structures are available. Compared to other GPCR structures, the MT1 template structure has several limitations as it was in the inactive form despite the presence of the 2‐phenylmelatonin agonist, and it was heavily modified with 9 point mutations and several truncations to facilitate expression and stability (7,8). However, a favorable feature of MT1 for virtual docking might be its ligand binding pocket which is rather small and hydrophobic with only two key residues important for high-affinity binding. This limits the number of poses to be screened by virtual docking. Moreover, although the screening was designed to identify MT1 selective compounds, positive hits included also MT2 selective and non-selective compounds suggesting that virtual screening is currently unable to predict type selective compounds. This might also depend on the quality of the receptor structure and the degree of divergence between receptor types.
In conclusion, this article is a nice example of successful virtual screening on GPCRs, one of the desired benefits of crystal structures, that will accelerate the drug development process towards compounds with improved efficacy and target-selectivity.
This study investigated two MT1-selective inverse agonists, UCSF7447 and UCSF3384, and a selective MT2 agonist, UCSF4226, for their affinities.
Comments by Ralf Jockers, Institut Cochin, CNRS, INSERM, Université de Paris, Paris, France, Chair for NC-IUPHAR Subcommitee for Melatonin receptors.
- Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010;62(3):343-380.
- Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on Melatonin Receptors. IUPHAR Review. Br J Pharmacol. 2016;173(18):2702-2725
- Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-383.
- Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol. 2017;175:3263–3280.
- Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA. MT1 and MT2 Melatonin Receptors: Ligands, Models, Oligomers, and Therapeutic Potential. J Med Chem. 2014;57(8):3161-3185.
- Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, Gati C, Batyuk A, Slocum ST, Ishchenko A, Brehm W, White TA, Michaelian N, Madsen C, Zhu L, Grant TD, Grandner JM, Shiriaeva A, Olsen RHJ, Tribo AR, Yous S, Stevens RC, Weierstall U, Katritch V, Roth BL, Liu W, Cherezov V. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature. 2019;569(7755):284-288.
- Stein RM, Kang HJ, McCorvy JD, Glatfelter GC, Jones AJ, Che T, Slocum S, Huang XP, Savych O, Moroz YS, Stauch B, Johansson LC, Cherezov V, Kenakin T, Irwin JJ, Shoichet BK, Roth BL, Dubocovich ML. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature. 2020. [PMID: 32040955]
- Cecon E, Liu L, Jockers R. Melatonin receptor structures shed new light on melatonin research. J Pineal Res. 2019:e12606.
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