A collaborative research team including members from University of California, San Francisco (UCSF), the University of North Carolina at Chapel Hill (UNC), and University of Buffalo (UB) have utilized a vast and novel computational library the first molecules that can modulate circadian rhythms with high selectivity to the MT1 melatonin receptor in the biological clock—located in the hypothalamus at the base of the brain. This research team pursues a key to unlocking why circadian rhythms malfunction and how the hormone melatonin, which is produced in the brain, can facilitate the development of targeted therapies that can mimic or counteract the actions of melatonin which is implicated in numerous circadian disorders ranging from depression and blindness to sleep disorders.
As reported in UBNow by Ellen Goldbaum and its publishing in the journal Nature, disorders such as insomnia and depression to obesity and bipolar disorder weak havoc on the lives of many millions of people. As it turns out, the behaviors regulated by the circadian rhythms, such as digestion and sleep-wake cycles, go unnoticed by most people but when they malfunction it can be the cause of inordinate suffering, for those that can’t sleep can attest.
Implications for this Research
As reported on by Ms. Goldbaum at UBNow, the three corresponding authors believe the findings represent a “confluence of major, complementary achievements and expertise” at the three research institutions collaborating on this research—some key findings:
· The discovery of ligands unknown to any known melatonin receptor ligands through the computational docking (simulating three-dimensional binding) of more than 150 million diverse, “make-on-demand” molecules (USF)
· The discovery of these molecules (UCSF 7447 and UCSF 3384) which never existed before, attach with high strength and selectivity to human or mouse MT1 melatonin receptors engineered in cells to produce cellular responses to either decrease as melatonin or increase MT1—mediated responses that provided the rational for the mouse circadian behavior studies (UNC)
· The discovery that the cellular responses seen in vitro translated directly to in vivo function, slowing down adjustment to a new environmental light/dark period in the mouse model of jet lag, with one unexpected finding demonstrating that they mimic melatonin to modulate rhythms in the absence of light cues (UB)
Margarita L. Dubocovich, a corresponding author and SUNY Distinguished Professor, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences at UB, declared, “This discovery allows us to now focus on the development of unique new molecules to generate a response that will help bring sleep patterns and other biological rhythms in line with environmental light and dark cycles, providing the sense of well-being that is only experienced when such rhythms are in sync.”
The Quest to Discover MT1 Ligands
UB’s Dubocovich has been pursuing the quest to discover MT1 ligands for fifteen years, reports Ms. Goldbaum. The ultimate goal of this fascinating pursuit centers on the discovery and development of drugs that address the devastating disorders that can occur when the circadian rhythms are disrupted. In this complex and lengthy quest, the three participating institutions each contribute important, value-added research—for example the availability of UCSF’s vast virtual library or what Dubocovich calls a “gold mine” of millions of molecules with distinct shapes that in many cases haven’t been synthesized or even seen in nature.
Margarita L. Dubocovich, a lead author and SUNY Distinguished Professor, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences at UB
Brian K. Shoichet, professor, Department of Pharmaceutical Chemistry, UCSF
Bryan L. Roth, Michael Hooker Distinguished Professor UNC School of Medicine
Call to Action: The researchers, according to UB’s Dubocovich, will set up preclinical-based studies that help them better pinpoint the molecular and signaling pathways that translate the response exerted by these molecules from the point that they interact with the receptors in the biological clock to the actual circadian behavior expressed in a mouse or human.