Melatonin is the principle hormone of the pineal gland that regulates mammalian circadian system. Both melatonin receptors MT1 and MT2 receptors bind melatonin with high affinity. Luzindole is a competitive antagonist of melatonin that binds both MT1 and MT2 receptors. A key structural feature responsible for melatonin and luzindole binding is an indole ring and in the case of luzindole a cyclohexyl ring. Flexible linkage between these two moieties allows binding to dual hydrophobic patches on either receptors. A suitable starting point for developing receptor specific compounds is therefore to emulate the positioning of ring structures akin to these compounds while fine tuning interactions through ring size and linker rigidity. Alignment of MT1 (human, hamster, mouse, sheep) or MT2 (human, partial mouse) sequences with bovine rhodopsin revealed the residues conserved within the subfamily of melatonin receptors, which may be implicated in ligand binding and receptor activation. In an initial docking study, in which the native ligand melatonin was allowed to sample the entire receptor interior using Flexidock (Tripos inc.,), the generated conformations were checked/filtered with reported mutational data to select a reference docked pose. The comparison with rhodopsin suggests binding site plasticity capable of accommodating a wider spectrum of ligands. We explored the possibility of generating more accurate and predictive models of melatonin receptors based on a reported x-ray crystal structure using an MD-based approach developed in our laboratory. The current findings suggest a dimeric, synthetically-amenable scaffold that can serve as a platform for selective targeting of MT1.

Dimeric two-ring scaffolds for selective targeting of human melatonin receptors MT<sub>1</sub> and MT<sub>2</sub>

248th National Meeting (2014)

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Dimeric two-ring scaffolds for selective targeting of human melatonin receptors MT1 and MT2

Dimeric two-ring scaffolds for selective targeting of human melatonin receptors MT₁ and MT₂