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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 …