2-Arylmelatonin analogues: Probing the 2-phenyl binding pocket of melatonin MT1 and MT2 receptors

In crystal structures of melatonin MT1 and MT2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT2 receptor. A...

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Published in:European journal of medicinal chemistry 2022-12, Vol.243, p.114762-114762, Article 114762
Main Authors: Mari, Michele, Elisi, Gian Marco, Bedini, Annalida, Lucarini, Simone, Retini, Michele, Lucini, Valeria, Scaglione, Francesco, Vincenzi, Fabrizio, Varani, Katia, Castelli, Riccardo, Mor, Marco, Rivara, Silvia, Spadoni, Gilberto
Format: Article
Language:English
Subjects:
Atropisomer
Free-energy simulations
Indole derivatives
Lipophilicity
Melatonin
MT1 and MT2 receptors
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Summary:In crystal structures of melatonin MT1 and MT2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT2 receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket. Thermodynamic integration simulations applied to MT1 and MT2 receptors in complex with the α-naphthyl derivative provided a rationale for the MT2-selectivity and investigation on the binding mode of a couple of atropisomers allowed to define the available space and arrangement of substituents inside the subpocket. Interestingly, more hydrophilic 2-aza-substituted compounds displayed high binding affinity and molecular dynamics simulations highlighted polar interaction with residues from the subpocket that could be responsible for their potency. [Display omitted] •The MT1/MT2 receptor binding site was investigated through 2-arylindole ligands.•An out-of-plane arrangement of the 2-substituent gave MT2-selective ligands.•Thermodynamic integration simulations rationalized the MT2-selectivity.•Atropisomers Ra-12 and Sa-12 revealed multiple arrangements in the subpocket.•Polar substituents are permitted in the subpocket and give high binding affinity.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114762