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Article

Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2

by
Mattia Cantarini
1,
Dario Rusciano
2,
Rosario Amato
3,
Alessio Canovai
3,
Maurizio Cammalleri
3,
Massimo Dal Monte
3,
Cristina Minnelli
1,
Emiliano Laudadio
4,
Giovanna Mobbili
1,
Giorgia Giorgini
1 and
Roberta Galeazzi
1,*
1
Department DISVA, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
2
Fidia Pharma Group, Research Center, 95100 Catania, Italy
3
Department of Biology, University of Pisa, 56127 Pisa, Italy
4
Department SIMAU, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(3), 2863; https://doi.org/10.3390/ijms24032863
Submission received: 13 January 2023 / Revised: 30 January 2023 / Accepted: 31 January 2023 / Published: 2 February 2023
(This article belongs to the Collection Feature Papers in Molecular Pharmacology)
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Abstract

Glaucoma, a major ocular neuropathy originating from a progressive degeneration of retinal ganglion cells, is often associated with increased intraocular pressure (IOP). Daily IOP fluctuations are physiologically influenced by the antioxidant and signaling activities of melatonin. This endogenous modulator has limited employment in treating altered IOP disorders due to its low stability and bioavailability. The search for low-toxic compounds as potential melatonin agonists with higher stability and bioavailability than melatonin itself could start only from knowing the molecular basis of melatonergic activity. Thus, using a computational approach, we studied the melatonin binding toward its natural macromolecular targets, namely melatonin receptors 1 (MT1) and 2 (MT2), both involved in IOP signaling regulation. Besides, agomelatine, a melatonin-derivative agonist and, at the same time, an atypical antidepressant, was also included in the study due to its powerful IOP-lowering effects. For both ligands, we evaluated both stability and ligand positioning inside the orthosteric site of MTs, mapping the main molecular interactions responsible for receptor activation. Affinity values in terms of free binding energy (ΔGbind) were calculated for the selected poses of the chosen compounds after stabilization through a dynamic molecular docking protocol. The results were compared with experimental in vivo effects, showing a higher potency and more durable effect for agomelatine with respect to melatonin, which could be ascribed both to its higher affinity for hMT2 and to its additional activity as an antagonist for the serotonin receptor 5-HT2c, in agreement with the in silico results.
Keywords: melatonin receptors; glaucoma; melatonergic agonists; molecular docking; molecular dynamics; drug design melatonin receptors; glaucoma; melatonergic agonists; molecular docking; molecular dynamics; drug design

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MDPI and ACS Style

Cantarini, M.; Rusciano, D.; Amato, R.; Canovai, A.; Cammalleri, M.; Monte, M.D.; Minnelli, C.; Laudadio, E.; Mobbili, G.; Giorgini, G.; et al. Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2. Int. J. Mol. Sci. 2023, 24, 2863. https://doi.org/10.3390/ijms24032863

AMA Style

Cantarini M, Rusciano D, Amato R, Canovai A, Cammalleri M, Monte MD, Minnelli C, Laudadio E, Mobbili G, Giorgini G, et al. Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2. International Journal of Molecular Sciences. 2023; 24(3):2863. https://doi.org/10.3390/ijms24032863

Chicago/Turabian Style

Cantarini, Mattia, Dario Rusciano, Rosario Amato, Alessio Canovai, Maurizio Cammalleri, Massimo Dal Monte, Cristina Minnelli, Emiliano Laudadio, Giovanna Mobbili, Giorgia Giorgini, and et al. 2023. "Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2" International Journal of Molecular Sciences 24, no. 3: 2863. https://doi.org/10.3390/ijms24032863

APA Style

Cantarini, M., Rusciano, D., Amato, R., Canovai, A., Cammalleri, M., Monte, M. D., Minnelli, C., Laudadio, E., Mobbili, G., Giorgini, G., & Galeazzi, R. (2023). Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2. International Journal of Molecular Sciences, 24(3), 2863. https://doi.org/10.3390/ijms24032863

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