1. 2-Arylmelatonin analogues: Probing the 2-phenyl binding pocket of melatonin MT 1 and MT 2 receptors.
- Author
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Mari M, Elisi GM, Bedini A, Lucarini S, Retini M, Lucini V, Scaglione F, Vincenzi F, Varani K, Castelli R, Mor M, Rivara S, and Spadoni G
- Subjects
- Ligands, Molecular Dynamics Simulation, Melatonin analogs & derivatives, Melatonin chemistry, Melatonin metabolism, Receptor, Melatonin, MT1 chemistry, Receptor, Melatonin, MT1 metabolism, Receptor, Melatonin, MT2 chemistry, Receptor, Melatonin, MT2 metabolism
- Abstract
In crystal structures of melatonin MT
1 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)- Published
- 2022
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