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New Tools and Surprising Results Pave the Way to More Comprehensive Understanding of Melatonin and Circadian Rhythm

In an important new study, scientists have combined computer modeling, chemical synthesis and refinement, and validation in animal models to identify novel compounds modulating melatonin receptor activity—advancing our ability to develop therapeutics that could help address health problems related to sleep and metabolism. Normally, the body uses a complex biological system, called the circadian rhythm or “body clock,” to help govern many physiological functions throughout the day and night. For this to work, the internal circadian rhythm needs to be synchronized to external day-night (light-dark) cycles. The hormone melatonin is key to this synchrony. In response to changing light levels, the brain produces more melatonin at night, which in people induces physiological changes that promote sleep, and less during the day, which stimulates wakefulness. Disruptions to normal circadian rhythm contribute to metabolic diseases such as diabetes and obesity, along with sleep disorders and other conditions, such as depression and increasing incidence of cardiovascular diseases. Thus, a better understanding of circadian biology and improved therapeutics are needed—and melatonin activity is a key target. Two cellular receptors for melatonin, MT1 and MT2, are known, but it has been unclear whether these might have different functions when bound to melatonin, or whether drugs designed to target one or the other might have different effects.

To gain further insights, researchers decided to synthesize molecules that actively and selectively bind one or the other of these melatonin receptors. To do this, the research team used a virtual jigsaw puzzle piece approach. As a first step, they took the known three-dimensional structure of human MT1 and, using computer modeling, screened over 150 million virtual molecules to find ones predicted to fit well into MT1’s melatonin binding site. Based on the results, they synthesized a subset of compounds to test in the laboratory, focusing on compounds with high selectivity at a very low concentration. After synthesizing and testing 38 compounds, the scientists found 15 new chemical structures that interacted well with either MT1, the very similar MT2, or both. As a key goal was to find molecules that could selectively engage with the subtypes of melatonin receptors and thereby enable probing of each receptor’s biological activities in animal models, the researchers chemically tweaked some of the 15 chemical structures and studied 3 of the resulting compounds. Two of these interacted selectively with MT1, and one interacted selectively with MT2. Among the exciting and unexpected results from circadian rhythm experiments in two different mouse models, the scientists found that the MT1-selective molecules could either block or mimic melatonin’s effects, depending upon the experiment—providing new insight into how melatonin works through its receptors. For example, the researchers found that administration of the MT1-selective molecules at experimentally-defined “dusk” caused the mice to change their normal behaviors in ways similar to the effect of administering melatonin itself. The study validates a powerful approach to finding novel, valuable compounds for investigating circadian biology and for potential development as therapeutics for diseases influenced by circadian rhythm—an approach that can be extended to other areas of investigation as well.

Stein RM, Kang HJ, McCorvy JD,…Dubocovich ML. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature 579: 609-614, 2020.