A New Tick on the Clock: Indole-Based Optimization of Melatonin Receptor Modulators

Objective: Melatonin is a key regulator of circadian rhythms and sleep-wake cycles, exerting its effects through MT1 and MT2 receptors. Despite the clinical use of selective MT1/MT2 agonists, their short half-lives, low bioavailabilities, and rapid first-pass metabolism limit their efficacy in sleep and circadian rhythm disorders. This study aimed to identify and evaluate novel piperazine-substituted indole derivatives with enhanced receptor binding, prolonged systemic circulation, and improved pharmacokinetic properties as potential next-generation melatonin receptor modulators.Methods: Seven piperazine-substituted indole derivatives were selected based on structure-activity relationship studies and structural similarity to melatonin. Molecular docking was conducted using AutoDock 4.2, followed by molecular dynamics (MD) simulations in GROMACS 2023.1 to assess receptor-ligand stability. Binding free energy calculations (molecular mechanics/Poisson–Boltzmann surface area [MM/PBSA] method) were performed to quantify ligand-receptor interactions. Pharmacokinetic properties were predicted using ADMETlab 2.0.Results: Among the tested compounds, 3-{[4-(1-Naphthylmethyl)piperazin-1-yl]methyl}-1<i>H</i>-indole, 3-{[4-(2,5-Dimethylphenyl) piperazin-1-yl]methyl}-1<i>H</i>-indole, and 3-{[4-(4-Acetylphenyl)piperazin-1-yl]methyl}-1<i>H</i>-indole exhibited the highest binding affinities for MT1 and MT2 receptors, with MM/PBSA free energies significantly lower than those of reference compound, ramelteon. MD simulations confirmed stable ligand-receptor interactions, with low root-mean-square deviation values over 100 ns, indicating minimal structural fluctuations. The tested derivatives demonstrated enhanced pharmacokinetic profile and minimal toxicity risks, suggesting greater therapeutic potential for circadian rhythm modulation.Conclusion: The identified piperazine-substituted indole derivatives demonstrated strong receptor binding, enhanced bioavailability, and prolonged half-life. These findings suggested that these derivatives hold promise for circadian rhythm-related disorders and sleep disturbances.